CN107849042A - Bicyclic heterocycle derivatives - Google Patents

Bicyclic heterocycle derivatives Download PDF

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CN107849042A
CN107849042A CN201680045062.1A CN201680045062A CN107849042A CN 107849042 A CN107849042 A CN 107849042A CN 201680045062 A CN201680045062 A CN 201680045062A CN 107849042 A CN107849042 A CN 107849042A
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compound
formulas
pharmaceutically acceptable
phenyl
mixture
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CN107849042B (en
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H-P.布赫施塔勒
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

Formulas I a or Formulas I b compound are the inhibitor of pyruvic dehydrogenase kinase (PDHK), and available for the particularly such as treatment of the disease of cancer, wherein, X, Y, R1And R2With the implication as shown in claim 1.

Description

Bicyclic heterocycle derivatives
Technical field
The present invention relates to new bicyclic heterocycle derivatives, the medicine containing them for suppressing pyruvic dehydrogenase kinase (PDHK) Composition, their preparation method and their purposes in treatment of cancer.
Background of invention
Pyruvic dehydrogenase kinase (also referred to as pyruvic dehydrogenase complex kinase, PDC kinases or PDHK) is a kind of kinases, and it passes through Inactivator (pyruvic dehydrogenase) is played a part of to its phosphorylation using ATP.
Therefore, PDHK take part in the regulation that pyruvic dehydrogenase is the pyruvate dehydrogenase complex of the first component.PDHK It is all located at pyruvate dehydrogenase complex in Eukaryotic mitochondrial matrix.In citrate cycle, the compound plays Pyruvic acid (product of sugar solution in cytosol) is converted into the effect of acetyl coenzyme A, it is then aoxidized to produce in mitochondria Raw energy.By adjusting the activity of the compound downwards, PDHK reduces the oxidation of pyruvic acid in mitochondria, and improves cytosol Conversion of the middle pyruvic acid to lactic acid.
The dephosphorylation of PDHK adverse effect, i.e. pyruvic dehydrogenase and activation, by being referred to as pyruvic dehydrogenase phosphorus The phosphoprotein phosphatase catalysis of sour enzyme.
(pyruvic dehydrogenase kinase should not be obscured with phosphoinositide dependant kinase -1, and it is also sometimes referred to as “PDK1”。)
PDHK isodynamic enzymes known to four kinds in side chain be present：PDHK1~PDHK4.
Some researchs show that the cell for lacking insulin (or to insulin insensitivity) is overexpressed PDHK4.Thus, solved by sugar The pyruvic acid of formation can not be oxidized, and this can cause hyperglycemia because glucose in blood can not be efficiently used.Therefore, it is several Kind targeting PDHK4 medicine is expected to treat type ii diabetes.
The presence due to HIF-1 is proved, PDHK1 has increased activity in hypoxemia cancer cell.PDHK1 is from citric acid Pyruvic acid is shunted in circulation, and keeps hypoxic cell to survive.Therefore, because PDHK1 prevents the Apoptosis in these cancer cells, So PDHK1 suppresses to have been proposed as antineoplaston.Similarly, it has therefore proved that PDHK3 crosses table in colon carcinoma cell line Reach.The three kinds of inhibitor proposed are the AZD7545 and dichloroacetate that are combined with PDHK1, and the red shell of root combined with PDHK3 Rhzomorph.
By suppressing PDHK activity to increase the PDC of activity form be the medicine target for diabetes, heart disease and cancer Mark.
The A1 of EP 2 345 629 disclose PDHK inhibitor, and it is considered to be useful for treating or preventing and glucose utilization Disorderly relevant disease, such as diabetes (such as type 1 diabetes, diabetes B etc.), insulin resistance syndrome, metabolism are comprehensive Simulator sickness, hyperglycaemia and hyperlactacidemia.In addition, PDHK inhibitor is considered to be useful for treating or preventing diabetic complication (example Such as DPN, PVR, nephrosis, cataract).In addition, PDHK inhibitor is considered to be useful for or prevented by group The caused disease of the limited energy substrate supply knitted, such as heart failure, cardiomyopathy, myocardial ischemia, dyslipidemia and dynamic Pulse atherosclerosis.In addition, PDHK inhibitor is considered to be useful for treating or preventing cerebral ischemia or cerebral apoplexy.In addition, PDHK suppresses Agent is considered to be useful for treating or preventing mitochondrial disease, mitochondrial encephalomyopathy, cancer etc..It is also contemplated that it can be used for treating Or prophylaxis of pulmonary hypertension.
Document：
Wikipedia, pyruvate dehydrogenase kinase；
T.E. Roche et al., Cell. Mol. Life Sci. 64 (2007) 830-849；
A. Kumar et al., Chemico-Biological Interactions 199 (2012) 29-37；
I.Papandreou et al., Int. J. Cancer: 128, 1001-1008 (2011)；
G. Sutendra et al., frontiers in oncology, 2013, vol. 3, 1-11。
It is an object of the invention to the noval chemical compound for finding to have valuable property, can be especially useful for preparing medicine Compound.
It has been found that compound of the invention and its salt while being well tolerated, have very valuable pharmacological Matter.
Present invention relates particularly to compound, the group comprising these compounds for the Formulas I a or Ib for suppressing PDHK, preferably PDHK2 Compound and for treat PDHK induction disease and symptom method.
Formulas I a or Ib compound can be additionally used in PDHK activity or the separation and research of expression.In addition, they are especially suitable Share in the diagnostic method of the disease related to the imbalance of PDHK activity or interference.
Host or patient can belong to any mammalian species, such as primate (particularly people), rodent are (including small Mouse, rat and hamster), rabbit, horse, ox, dog, cat etc..Animal model has the benefit of experimental study, there is provided for treating mankind's disease The model of disease.
Specific cell can be determined by testing in vitro to the neurological susceptibility treated with the compounds of this invention.Generally cell is trained Support thing and a period of time is mixed with the compounds of this invention of various concentration, the time is enough to allow activating agent (such as anti-IgM) to induce Cell effect (expression of such as surface marker), generally between about 1 hour and 1 week.It can be used and carry out autoblood or from group living Knit and check that the culture cell of sample carries out testing in vitro.The amount of expressed surface marker uses identification by flow cytometry The specific antibody of the label is evaluated.
Dosage changes according to particular compound used, disease specific, patient's states etc..Therapeutic dose is typically enough to show The undesirable cell group reduced in target tissue is write, while the viability of patient is maintained.Treatment is typically continue until that appearance is notable Reduce, such as cell burden reduces at least about 50%, and treat sustainable until no longer detecting undesirable cell substantially in vivo.
Prior art
The bicyclic pyrazolo Hete rocyclic derivatives for treating pain and inflammation are described in WO 2010/085050.
Other bicyclic heterocycles as kinases inhibitor are described in WO 2009/143447.
Other Pyrazolopyridines for treating inflammation are described in US 3423414.
Summary of the invention
The present invention relates to Formulas I a or Formulas I b compound and its pharmaceutically acceptable salt, dynamic isomer and stereoisomer, Mixture including its all proportions：
Wherein,
X represents CH or N,
Y represents CH or N,
R1Represent H, A, (CH2)nAr、(CH2)nHet or Cyc,
R2Represent H or CH3,
Ar represents phenyl, and it is unsubstituted or with Hal, A, CN, OA, [C (R5)2]POH、[C(R5)2]pN(R5)2、NO2、[C (R5)2]pCOOR5、NR5COA、NR5SO2A、[C(R5)2]pSO2N(R5)2、S(O)nA、O[C(R5)2]mN(R5)2、NR5COOA、 NR5CON(R5)2And/or COA is monosubstituted, two substitute, three substitute, four substitute or five substitutions,
Het represents single-or bicyclic saturation, undersaturated or aromatics the heterocycle with 1 ~ 4 N, O and/or S atom, and it is not It is substituted or with Hal, A, CN, OA, [C (R5)2]pOH、[C(R5)2]pN(R5)2、NO2、[C(R5)2]pCOOR5、NR5COA、 NR5SO2A、[C(R5)2]pSO2N(R5)2、S(O)nA、O[C(R5)2]mN(R5)2、NR5COOA、NR5CON(R5)2And/or COA is mono- takes Generation or two substitutions,
Cyc represents the cycloalkyl with 3,4,5,6 or 7 C- atoms, and it is unsubstituted or monosubstituted with OH,
A represents the non-branched or branched alkyl with 1 ~ 10 C- atom, wherein 1 or 2 CH- and/or CH not adjoined2- base It can be substituted by N- atoms, O- atoms and/or S- atoms, and/or wherein 1 ~ 7 H- atom can be by R4Substitution,
R4F, Cl or OH are represented,
R5H or A ' is represented,
A ' represents the non-branched or branched alkyl with 1 ~ 6 C- atom, wherein 1 ~ 5 H- atom can be substituted by F,
Hal represents F, Cl, Br or I,
M represents 1,2,3 or 4,
N represents 0,1 or 2,
P represents 0,1,2,3 or 4,
On condition that
If X=CH, Y=N, or
If Y=CH, X=N.
The invention further relates to optical active forms of above-claimed cpd (stereoisomer), enantiomer, racemic modification, non-right Reflect body and hydrate and solvate.
In addition, the present invention relates to the pharmaceutically acceptable derivates of Formulas I a or Ib compound.
The solvate of term compound refers to inert solvent molecules adduction to compound, and it is because of their mutual attractions Power and formed.Solvate is such as monohydrate or dihydrate or alcohol adduct.It will be understood that the present invention also relates to above-mentioned The solvate of salt.Term pharmaceutically acceptable derivates refer to the salt of such as the compounds of this invention and so-called prodrug chemical combination Thing.
Unless otherwise indicated, as used herein term " prodrug " refers to the derivative of Formulas I a or Ib compound, and it can (external or in vivo) hydrolysis, oxidation or otherwise reacted under biotic factor, there is provided reactive compound, particularly Formulas I a or Ib compound.The example of prodrug includes but is not limited to, the derivative and metabolite of Formulas I a or Ib compound, and it includes life Thing hydrolyzable moiety, such as biological hydrolyzable acid amides, the hydrolyzable ester of biology, the hydrolyzable carbamate of biology, biology can Carbonic ester, the hydrolyzable uride of biology and the hydrolyzable phosphate analog of biology of hydrolysis.In certain embodiments, have The prodrug of the compound of carboxyl functional group is the lower alkyl esters of carboxylic acid.The carboxylate is by being esterified any carboxylic present on molecule Acid moieties and easily form.Prodrug can be prepared by using known method, such as Burger ' s Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H.Bundgaard ed., 1985, Harwood Academic Publishers Gmfh) described in method.
The amount that " effective dose " represents medicine or active component pharmaceutically is stated, it is in tissue, system, animal or side chain The biology or medical response for causing such as researcher or doctor to find or need.
In addition, statement " effective dose in treatment " is represented compared with the corresponding subject for not receiving the amount, have following As a result amount：
Disease, syndrome, situation, sufferer, improved treatment, healing, prevention or the elimination of illness or side effect, and disease, The reduction of the development of sufferer or illness.
Statement " therapeutically effective amount " also includes the amount for being effectively increased normal physiological function.
The invention further relates to the mixture of Formulas I a or Ib compound, such as the mixture of two kinds of diastereoisomers, example If ratio is 1:1、1:2、1:3、1:4、1:5、1:10、1:100 or 1:The use of the mixture of 1000 two kinds of diastereoisomers On the way.
The mixture of the particularly preferred Stereoisomeric compounds of these compounds.
" dynamic isomer " refers to the isomeric forms of the compound each other in balance.The concentration of isomeric forms Depending on environment existing for compound, and can be according to such as compound solid or in the organic or aqueous solution it is different.
The present invention relates to Formulas I a or Ib compound and its salt, and compound for formula Ia or Ib and its pharmaceutically Acceptable salt, solvate, the method for dynamic isomer and stereoisomer, methods described be characterised by, make Formula II a or IIb compound and the compound of formula III are reacted, and/or the alkali of Formulas I or acid are converted into one kind of its salt：
Wherein, X, Y, R1And R2With the implication as shown in claim 1；
Wherein, L represents the OH bases of Cl, Br, I or free or reactive function sex modification.
In the above and below, unless expressly stated otherwise, atomic group X, Y, R1And R2With containing as shown in Formulas I a or Ib Justice.
A represents alkyl, and it is non-branched (linear) or side chain, and has 1,2,3,4,5,6,7,8,9 or 10 C Atom.A preferably represents methyl, also including ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group, in addition to penta Base, 1- methyl butyls, 2- methyl butyls or 3- methyl butyls, 1,1- dimethyl propyl, 1,2- dimethyl propyls or 2,2- diformazan Base propyl group, 1- ethyl propyls, hexyl, 1- methyl amyls, 2- methyl amyls, 3- methyl amyls or 4- methyl amyls, 1,1- diformazan Base butyl, 1,2- dimethylbutyls, 1,3- dimethylbutyls, 2,2- dimethylbutyls, 2,3- dimethylbutyls or 3,3- diformazans Base butyl, 1- ethyl-butyls or 2- ethyl-butyls, 1- ethyl -1- methyl-propyls, 1- Ethyl-2-Methyl propyl group, 1,1,2- front three Base propyl group or 1, more preferably 2,2- thmethylpropyls, such as trifluoromethyl.
A is preferred to represent non-branch or branch the alkyl with 1 ~ 10 C- atom, wherein 1 or 2 CH- not adjoined And/or CH2- base can be substituted by N- and/or O- atoms, and wherein 1 ~ 7 H- atom can be by R4Substitution.
A particularly preferably represents the alkyl with 1,2,3,4,5 or 6 C atom, preferably methyl, ethyl, propyl group, isopropyl, Butyl, isobutyl group, sec-butyl, the tert-butyl group, phenyl, hexyl, trifluoromethyl, pentafluoroethyl group or 1,1,1- trifluoroethyls.
In addition, A preferably represents CH2OCH3, CH2CH2OH or CH2CH2OCH3.Cyc represents cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl or suberyl, preferably it is unsubstituted or monosubstituted with OH.
A ' represents alkyl, and it is non-branched (linear) or side chain, and has 1,2,3,4,5 or 6 C atom.A’ It is preferred that methyl is represented, also including ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group, in addition to amyl group, 1- Methyl butyl, 2- methyl butyls or 3- methyl butyls, 1,1- dimethyl propyl, 1,2- dimethyl propyls or 2,2- dimethyl propylene Base, 1- ethyl propyls, hexyl, 1- methyl amyls, 2- methyl amyls, 3- methyl amyls or 4- methyl amyls, 1,1- dimethyl butyrate Base, 1,2- dimethylbutyls, 1,3- dimethylbutyls, 2,2- dimethylbutyls, 2,3- dimethylbutyls or 3,3- dimethyl butyrates Base, 1- ethyl-butyls or 2- ethyl-butyls, 1- ethyl -1- methyl-propyls, 1- Ethyl-2-Methyl propyl group, 1,1,2- trimethyl third Base or 1, further preferably 2,2- thmethylpropyls, such as trifluoromethyl.
A ' particularly preferably represents the alkyl with 1,2,3,4,5 or 6 C atom, wherein 1 ~ 3 H- atom can be substituted by F.
Ar preferably represents o- tolyl, m- tolyl or p- tolyl, o- ethylphenyl, m- ethylphenyl or p- Ethylphenyl, o- propyl group phenyl, m- propyl group phenyl or p- propyl group phenyl, o- isopropyl phenyl, m- isopropyl phenyl or P- isopropyl phenyl, o- tert-butyl-phenyl, m- tert-butyl-phenyl or p- tert-butyl-phenyl, o- hydroxy phenyl, m- hydroxyl Phenyl or p- hydroxy phenyl, o-nitrophenyl, m- nitrobenzophenone or p- nitrobenzophenone, o-amino-phenyl, m- aminobenzene Base or p- aminophenyl, o- (N- methylaminos) phenyl, m- (N- methylaminos) phenyl or p- (N- methylaminos) phenyl, O- (N- methylaminocarbonyls) phenyl, m- (N- methylaminocarbonyls) phenyl or p- (N- methylaminocarbonyls) phenyl, it is o- Methoxyphenyl, m- methoxyphenyl or p- methoxyphenyl, o- ethoxyl phenenyl, m- ethoxyl phenenyl or p- ethoxy Base phenyl, o- ethoxy carbonyl-phenyl, m- ethoxy carbonyl-phenyl or p- ethoxy carbonyl-phenyl, o- (N, N- diformazan Base amino) phenyl, m- (N, N- dimethylamino) phenyl or p- (N, N- dimethylamino) phenyl, o- (N, N- dimethyl- Amino carbonyl) phenyl, m- (N, N- dimethyl-aminocarbonyl) phenyl or p- (N, N- dimethyl-aminocarbonyl) phenyl, it is o- (N- ethylaminos) phenyl, m- (N- ethylaminos) phenyl or p- (N- ethylaminos) phenyl, o- (N, N- diethylamino) Phenyl, m- (N, N- diethylamino) phenyl or p- (N, N- diethylamino) phenyl, ortho-fluorophenyl base, m- fluorophenyl or P- fluorophenyl, o- bromophenyl, m- bromophenyl or p- bromophenyl, o- chlorphenyl, m- chlorphenyl or p- chlorphenyl are o- (sulfonyloxy methyl amido) phenyl, m- (sulfonyloxy methyl amido) phenyl or p- (sulfonyloxy methyl amido) phenyl, o- (methyl-sulphonyl Base) phenyl, m- (anethane-sulfonyl) phenyl or p- (anethane-sulfonyl) phenyl, o- cyano-phenyl, m- cyano-phenyl or P- cyano-phenyl, o- carboxyl phenyl, m- carboxyl phenyl or p- carboxyl phenyl, o- methoxycarbonyl-phenyl, m- methoxyl group Carbonyl phenyl or p- methoxycarbonyl-phenyl, o-acetyl base phenyl, m- acetylphenyl or p- acetylphenyl, o- ammonia Base-sulfonvlphenyl, m- amino-sulfonyl phenyl or p- amino-sulfonyl phenyl, o- [2- (morpholine -4- bases) ethyoxyl] Phenyl, m- [2- (morpholine -4- bases) ethyoxyl] phenyl or p- [2- (morpholine -4- bases) ethyoxyl] phenyl, o- [3- (N, N- bis- Ethylamino) propoxyl group] phenyl, m- [3- (N, N- diethylamino) propoxyl group] phenyl or p- [3- (N, N- diethyl aminos Base) propoxyl group] phenyl, further preferred 2,3- difluorophenyls, 2,4- difluorophenyls, 2,5- difluorophenyls, 2,6- difluorophenyls, 3,4- difluorophenyls or 3,5- difluorophenyl, 2,3- dichlorophenyls, 2,4- dichlorophenyls, 2,5- dichlorophenyls, 2,6- dichloro-benzenes Base, 3,4- dichlorophenyls or 3,5- dichlorophenyl, 2,3- dibromo phenyls, 2,4- dibromo phenyls, 2,5- dibromo phenyls, 2,6- dibromos Phenyl, 3,4- dibromo phenyls or 3,5- dibromo phenyl, 2,4- dinitrophenyls or 2,5- dinitrophenyl, 2,5- dimethoxy benzenes Base or 3,4- Dimethoxyphenyl, 3- nitro -4- chlorphenyls, the chloro- phenyl of 3- amino -4-, the chloro- phenyl of 2- amino -3-, 2- ammonia The chloro- phenyl of base -4-, the chloro- phenyl of 2- amino -5- or 2- amino -6- chlorphenyls, 2- nitros -4-N, N- dimethyl-amino-phenyl or 3- nitros -4-N, N- dimethylaminophenyl, 2,3- diamino-phenyls, 2,3,4- trichlorophenyls, 2,3,5- trichlorophenyls, 2,3, 6- trichlorophenyls, 2,4,6- trichlorophenyls or 3,4,5- trichlorophenyls, 2,4,6- trimethoxyphenyls, 2- hydroxyl -3,5- dichloros Phenyl, p- iodophenyl, 3,6- bis- chloro- 4- aminophenyls, the fluoro- 3- chlorphenyls of 4-, the fluoro- 4- bromophenyls of 2-, 2,5- bis- fluoro- 4- bromines Phenyl, the bromo- 6- methoxyphenyls of 3-, the chloro- 6- methoxyphenyls of 3-, the chloro- 4- acetamidophenyls of 3-, the fluoro- 4- methoxybenzenes of 3- Base, 3- amino -6- aminomethyl phenyls, the chloro- 4- acetamidophenyls of 3- or 2,5- dimethyl -4- chlorphenyls.
Ar further preferably represents phenyl, and it is unsubstituted or with Hal, A, CN and/or OA be monosubstituted, two substitutions, three takes Generation, four substitutions or five substitutions.
Not considering further to substitute, Het represents such as 2- furyls or 3- furyls, 2- thienyls or 3- thienyls, 1- pyrrole radicals, 2- pyrrole radicals or 3- pyrrole radicals, 1- imidazole radicals, 2- imidazole radicals, 4- imidazole radicals or 5- imidazole radicals, 1- pyrazolyls, 3- Pyrazolyl, 4- pyrazolyls or 5- pyrazolyls, 2- oxazolyls, 4- oxazolyls or 5- oxazolyls, 3- isoxazolyls, 4- isoxazolyls or 5- isoxazolyls, 2- thiazolyls, 4- thiazolyls or 5- thiazolyls, 3- isothiazolyls, 4- isothiazolyls or 5- isothiazolyls, 2- pyrroles Piperidinyl, 3- pyridine radicals or 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals or 6- pyrimidine radicals, further preferred 1,2,3- Triazol-1-yl, 1,2,3-triazoles -4- bases or 1,2,3-triazoles -5- bases, 1,2,4- triazol-1-yl, 1,2,4- triazole -3- bases or 1,2,4- triazole -5- bases, 1- tetrazole radicals or 5- tetrazole radicals, 1,2,3- oxadiazole -4- bases or 1,2,3- oxadiazole -5- bases, 1,2, 4- oxadiazole -3- bases or 1,2,4- oxadiazole -5- bases, 1,3,4- thiadiazoles -2- bases or 1,3,4- thiadiazoles -5- bases, 1,2,4- Thiadiazoles -3- bases or 1,2,4- thiadiazoles -5- bases, 1,2,3- thiadiazoles -4- bases or 1,2,3- thiadiazoles -5- bases, 3- pyridazinyls Or 4- pyridazinyls, pyrazinyl, 1- indyls, 2- indyls, 3- indyls, 4- indyls, 5- indyls, 6- indyls or 7- Yin Diindyl base, 4- isoindolyls or 5- isoindolyls, indazolyl, 1- benzimidazolyls, 2- benzimidazolyls, 4- benzimidazolyls or 5- Benzimidazolyl, 1- benzopyrazoles base, 3- benzopyrazoles base, 4- benzopyrazoles base, 5- benzopyrazoles base, 6- benzopyrazoles base or 7- benzopyrazoles bases, 2- benzoxazolyls, 4- benzoxazolyls, 5- benzoxazolyls, 6- benzoxazolyls or 7- benzoxazoles Base, 3- benzoisoxazoles base, 4- benzoisoxazoles base, 5- benzoisoxazoles base, 6- benzoisoxazoles base or 7- benzoisoxazoles Base, 2-[4-morpholinodithio base, 4- benzothiazolyls, 5- benzothiazolyls, 6- benzothiazolyls or 7- benzothiazolyls, 2- benzisoxas Thiazolyl, 4- benzisothias oxazolyl, 5- benzisothias oxazolyl, 6- benzisothias oxazolyl or 7- benzisothia oxazolyls, 4- benzo -2, 1,3- oxadiazolyls, 5- benzo -2,1,3- oxadiazolyls, 6- benzo -2,1,3- oxadiazolyls or 7- benzo -2,1,3- oxadiazoles Base, 2- quinolyls, 3- quinolyls, 4- quinolyls, 5- quinolyls, 6- quinolyls, 7- quinolyls or 8- quinolyls, 1- isoquinolin Base, 3- isoquinolyls, 4- isoquinolyls, 5- isoquinolyls, 6- isoquinolyls, 7- isoquinolyls or 8- isoquinolyls, 3- cinnolines Base, 4- cinnolines base, 5- cinnolines base, 6- cinnolines base, 7- cinnolines base or 8- cinnolines bases, 2- quinazolyls, 4- quinazolyls, 5- quinoline azoles Quinoline base, 6- quinazolyls, 7- quinazolyls or 8- quinazolyls, 5- quinoxalinyls or 6- quinoxalinyls, 2-2H- phendioxins, 4- Oxazinyl, 3-2H- phendioxins, 4- oxazinyls, 5-2H- phendioxins, 4- oxazinyls, 6-2H- phendioxins, 4- oxazinyls, 7-2H- benzene And-the oxazinyl of Isosorbide-5-Nitrae-or 8-2H- phendioxins, 4- oxazinyls, further preferred 1,3- benzodioxoles -5- bases, 1, 4- benzodioxan -6- bases, 2,1,3- diazosulfide -4- bases, 2,1,3- diazosulfide -5- bases or 2,1,3- Ben Bing Evil bis- Azoles -5- bases, azabicyclo [3.2.1] octyl group or dibenzofuran group.
Above-mentioned heteroatom group also can partly or wholly be hydrogenated.
Therefore, do not consider further to substitute, Het may also indicate that such as 2,3- dihydro -2- furyls, 2,3- dihydros -3- Furyl, 2,3- dihydro -4- furyls or 2,3- dihydro -5- furyls, 2,5- dihydro -2- furyls, 2,5- dihydro -3- furans Base, 2,5- dihydro -4- furyls or 2,5- dihydro -5- furyls, tetrahydrochysene -2- furyls or tetrahydrochysene -3- furyls, 1,3- dioxy Heterocycle pentane -4- bases, tetrahydrochysene -2- thienyls or tetrahydrochysene -3- thienyls, 2,3- dihydro -1- pyrrole radicals, 2,3- dihydro -2- pyrroles Base, 2,3- dihydro -3- pyrrole radicals, 2,3- dihydro -4- pyrrole radicals or 2,3- dihydro -5- pyrrole radicals, 2,5- dihydro -1- pyrrole radicals, 2,5- dihydro -2- pyrrole radicals, 2,5- dihydro -3- pyrrole radicals, 2,5- dihydro -4- pyrrole radicals or -5- pyrrole radicals, 1- pyrrolidinyls, 2- pyrrolidinyls or 3- pyrrolidinyls, tetrahydrochysene -1- imidazole radicals, tetrahydrochysene -2- imidazole radicals or tetrahydrochysene -4- imidazole radicals, 2,3- dihydro -1- Pyrazolyl, 2,3- dihydro -2- pyrazolyls, 2,3- dihydro -3- pyrazolyls, 2,3- dihydro -4- pyrazolyls or 2,3- dihydro -5- pyrazoles Base, tetrahydrochysene -1- pyrazolyls, tetrahydrochysene -3- pyrazolyls or tetrahydrochysene -4- pyrazolyls, Isosorbide-5-Nitrae-dihydro -1- pyridine radicals, Isosorbide-5-Nitrae-dihydro -2- pyrroles Piperidinyl, Isosorbide-5-Nitrae-dihydro -3- pyridine radicals or Isosorbide-5-Nitrae-dihydro -4- pyridine radicals, 1,2,3,4- tetrahydrochysene -1- pyridine radicals, 1,2,3,4- tetrahydrochysenes - 2- pyridine radicals, 1,2,3,4- tetrahydrochysene -3- pyridine radicals, 1,2,3,4- tetrahydrochysene -4- pyridine radicals, 1,2,3,4- tetrahydrochysene -5- pyridine radicals or 1,2,3,4- tetrahydrochysene -6- pyridine radicals, 1- piperidyls, 2- piperidyls, 3- piperidyls or 4- piperidyls, 2- morpholinyls, morpholinyl Or 4- morpholinyls, tetrahydrochysene -2- pyranoses, tetrahydrochysene -3- pyranoses or tetrahydrochysene -4- pyranoses, the alkyl dioxin of Isosorbide-5-Nitrae -, 1,3- bis- Evil Alkane -2- bases, 1,3- dioxane-4-yls or 1,3- dioxane -5- bases, hexahydro -1- pyridazinyls, hexahydro -3- pyridazinyls or hexahydro -4- Pyridazinyl, hexahydro -1- pyrimidine radicals, hexahydro -2- pyrimidine radicals, hexahydro -4- pyrimidine radicals or hexahydro -5- pyrimidine radicals, 1- piperazinyls, 2- piperazines Piperazine base or 3- piperazinyls, 1,2,3,4- tetrahydrochysene -1- quinolyls, 1,2,3,4- tetrahydrochysene -2- quinolyls, 1,2,3,4- tetrahydrochysene -3- quinolines Quinoline base, 1,2,3,4- tetrahydrochysene -4- quinolyls, 1,2,3,4- tetrahydrochysene -5- quinolyls, 1,2,3,4- tetrahydrochysene -6- quinolyls, 1,2,3, 4- tetrahydrochysene -7- quinolyls or 1,2,3,4- tetrahydrochysene -8- quinolyls, 1,2,3,4- tetrahydrochysene -1- isoquinolyls, 1,2,3,4- tetrahydrochysenes - 2- isoquinolyls, 1,2,3,4- tetrahydrochysene -3- isoquinolyls, 1,2,3,4- tetrahydrochysene -4- isoquinolyls, 1,2,3,4- tetrahydrochysenes -5- are different Quinolyl, 1,2,3,4- tetrahydrochysene -6- isoquinolyls, 1,2,3,4- tetrahydrochysene -7- isoquinolyls or 1,2,3,4- tetrahydrochysene -8- isoquinolin Base, 2-, 3-, 5-, 6-, 7- or 8-3,4- dihydro -2H- phendioxins, 4- oxazinyls (2-, 3-, 5-, 6-, 7-, or 8- 3, 4-dihydro-2H-benzo-1,4-oxazinyl), further preferred 2,3- methylenedioxyphenyls base, 3,4- methylene two Phenyl, 2,3- ethylenedioxyphenyls, 3,4- ethylenedioxyphenyls, 3,4- (epoxide of difluoro methylene two) benzene Base, 2,3- Dihydrobenzofuranes -5- bases or 2,3- Dihydrobenzofuranes -6- bases, 2,3- (2- oxos methylenedioxy) phenyl, Or 3,4- dihydro -2H-1,5- benzodioxepins -6- or -7- bases, further preferred 2,3- dihydro benzo furyls, 2, 3- dihydro-2-oxos furyl, 3,4- dihydro-2-oxo -1H- quinazolyls, 2,3- bis- hydrogen benzoxazolyl, 2- oxo -2, 3- bis- hydrogen benzoxazolyl, 2,3- dihydrobenzos imidazole radicals, 1,3- indoline, 2- oxo -1,3- indoline or 2- oxos - 2,3- dihydrobenzo imidazole radicals.
Het preferably represent pyrimidine radicals, pyridine radicals, pyridazinyl, pyrazinyl, piperidyl, pyrrolidinyl, pyrazolyl, thiazolyl, Imidazole radicals, furyl, thienyl, pyrrole radicals, oxazolyl, isoxazolyls, triazolyl, oxadiazolyls or thiadiazolyl group, they are each From be unsubstituted or with Hal, A and/or OA it is monosubstituted or two substitution.
Hal preferably represents F, Cl or Br, and it is also preferred that represents I, particularly preferred F or Cl.
In the present invention, all atomic groups for occurring more than 1 time may be the same or different, i.e., independently of one another.
Formulas I a or Ib compound can have one or more chiral centres, and can be therefore with various stereoisomeric forms in any ratio Occur.Formulas I a or Ib include all these forms.
Therefore, present invention is particularly directed to Formulas I a or Ib compound, wherein at least one in above-mentioned atomic group have it is upper State 1 in preferred meaning.The group of some preferable compounds can be used to lower sub- Formulas I aa ~ Iac expression, itself and Formulas I a or Ib Unanimously, and wherein described atomic group is not specified in more detail and has the implication of Formulas I a or Ib instruction, but wherein,
In Iaa, Ar represents phenyl, and it is unsubstituted or with Hal, A, CN and/or OA be monosubstituted, two substitutions, three substitutions, four takes Generation or five substitutions；
In Iab, Het represent pyrimidine radicals, pyridine radicals, pyridazinyl, pyrazinyl, piperidyl, pyrrolidinyl, pyrazolyl, thiazolyl, Imidazole radicals, furyl, thienyl, pyrrole radicals, oxazolyl, isoxazolyls, triazolyl, oxadiazolyls or thiadiazolyl group, they are each From be unsubstituted or with Hal, A and/or OA it is monosubstituted or two substitution；
In Iac, X represents CH or N,
Y represents CH or N,
R1Represent H, A, (CH2)nAr、(CH2)nHet or Cyc,
R2Represent H or CH3,
Ar represents phenyl, and it is unsubstituted or with Hal, A, CN and/or OA be monosubstituted, two substitutions, three substitutions, four substitutions or five takes Generation,
Het represent pyrimidine radicals, pyridine radicals, pyridazinyl, pyrazinyl, piperidyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazole radicals, Furyl, thienyl, pyrrole radicals, oxazolyl, isoxazolyls, triazolyl, oxadiazolyls or thiadiazolyl group, each of which is without taking Generation or with Hal, A and/or OA it is monosubstituted or two substitute,
Cyc represents the cycloalkyl with 3,4,5,6 or 7 C- atoms, and it is unsubstituted or monosubstituted with OH,
A represents the non-branched or branched alkyl with 1 ~ 10 C- atom, wherein 1 or 2 CH- and/or CH not adjoined2- base It can be substituted by N- atoms, O- atoms and/or S- atoms, and/or wherein 1 ~ 7 H- atom can be by R4Substitution,
R4F, Cl or OH are represented,
Hal represents F, Cl, Br or I,
N represents 0,1 or 2,
On condition that
If X=CH, Y=N, or
If Y=CH, X=N,
And its pharmaceutically acceptable salt, dynamic isomer and stereoisomer, include the mixture of its all proportions.
In addition, Formulas I a or Ib compound and for preparing their raw material by such as document (such as in standard operation In, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart) described in method known per se prepare, it is It is clear and definite to know and be suitable under the reaction condition of the reaction.No longer narration in detail herein can also be used herein Variant known per se.
Initial compounds for formula Ia or Ib compound are commonly known.If they are new, they It can be prepared by method known per se.
Formulas I a or Ib compound preferably by the compound that makes Formula II a or IIb and the compound of formula III react come Arrive.
In the compound of formula III, L preferably represents the OH bases of Cl, Br, I or free or reactive function sex modification, such as Such as the ester of activation, imidazolium compounds or alkylsulfonyloxy (preferably methyl-sulfonyloxy or trifluoro with 1 ~ 6 C atom Sulfonyloxy methyl epoxide) or aryl-sulfonyl oxygen (preferably phenyl-or p- tolylsulfonyl- epoxide) with 6 ~ 10 carbon atoms.
Reaction is generally acid binding agent, preferably organic base (such as DIPEA, triethylamine, dimethyl-aniline, pyridine or quinoline) In the presence of carry out.
Add alkali metal or alkaline earth oxide, carbonate or bicarbonate or another alkali metal or alkaline-earth metal The salt of weak acid of (preferably potassium, sodium, calcium or caesium) can also be favourable.
It is preferred that react in [dimethylamino-([1,2,3] triazol [4,5-b] pyrimidin-3-yl epoxide)-methylene]-two In the presence of methyl-ammonium hexafluorophosphate [HATU, coupling agent] or in the chloro- N of 1-, N, enter in the presence of 2- trimethyl -1- propionamides OK.
According to the condition used, the reaction time between a few minutes to 14 days, reaction temperature between about -30 ° to 140 °, Generally between -10 ° to 90 °, particularly between about 0 ° to about 70 °.
The example of suitable atent solvent be hydro carbons (such as hexane, petroleum ether, benzene, toluene or dimethylbenzene), chlorinated hydrocarbons (such as Trichloro ethylene, 1,2- dichloroethanes, carbon tetrachloride, chloroform or dichloromethane), alcohols (such as methanol, ethanol, isopropanol, positive third Alcohol, n-butanol or the tert-butyl alcohol), ethers (such as ether, diisopropyl ether, tetrahydrofuran (THF) Huo dioxanes), glycol ethers (such as second Glycol monomethyl or single ethylether, ethylene glycol dimethyl ether (diethylene glycol dimethyl ether (diglyme))), ketone (such as acetone or fourth Ketone), amide-type (such as acetamide, dimethyl acetamide or dimethylformamide (DMF)), nitrile (such as acetonitrile), sulfoxide type (such as Dimethyl sulfoxide (DMSO) (DMSO)), carbon disulfide, carboxylic acids (such as formic acid or acetic acid), nitro compound species (such as nitromethane or nitro Benzene), the mixture of esters (such as ethyl acetate) or the solvent.
Particularly preferred acetonitrile, dichloromethane and/or DMF.
Pharmaceutical salts and other forms
Compound of the present invention can be used with its final salt-independent shape.On the other hand, the present invention also includes these chemical combination The use of the pharmaceutically acceptable salt form of thing, the pharmaceutically acceptable salt can be by operations known in the art by each The organic and inorganic bronsted lowry acids and bases bronsted lowry of kind derives to obtain.The pharmaceutically acceptable salt form of Formulas I a or Ib compound is most of by normal It is prepared by rule method.If Formulas I a or Ib compound contain carboxyl, a kind of its suitable salt can by make the compound with it is suitable Alkali react to obtain corresponding base addition salts to be formed.Such alkali is such as alkali metal hydroxide (including potassium hydroxide, hydrogen Sodium oxide molybdena and lithium hydroxide), alkaline earth metal hydroxide (such as barium hydroxide and calcium hydroxide), alkali metal alcoholates (such as ethanol Potassium and sodium propoxide) and various organic bases (such as piperidines, diethanol amine and N- methylglutamines).The ammonium salt of Formulas I a or Ib compound Similarly it is included.In the case of Formulas I a or Ib some compounds, acid-addition salts can be by using pharmaceutically acceptable (such as hydrogen halides (such as hydrogen chloride, hydrogen bromide or hydrogen iodide), other inorganic and its corresponding salt are (such as the acid of organic or inorganic Sulfate, nitrate or phosphate etc.) and alkyl-and single arylsulphonate (such as esilate, toluene fulfonate and benzene sulfonic acid Salt) and other organic acids and its corresponding salt (such as acetate, trifluoroacetate, tartrate, maleate, succinate, Citrate, benzoate, salicylate, ascorbate etc.)) these compounds are handled to be formed.Therefore, Formulas I a or Ib The pharmaceutically acceptable acid-addition salts of compound include following：Acetate, adipate, alginate, arginine salt, asparagus fern Propylhomoserin salt, benzoate, benzene sulfonate (besylate), disulfate, bisulfites, bromide, butyrate, camphoric acid Salt, camsilate, caprylate, chloride, chloro benzoate, citrate, pentamethylene-propionate, digluconate, phosphoric acid Dihydric salt, dinitro-benzoate, dodecyl-sulphuric salt, esilate, fumarate, formates, galactolipin hydrochlorate (come From glactaric acid), galacturonic hydrochlorate, glucose enanthate, gluconate, glutamate, glycerophosphate, hemisuccinic acid salt, half sulphur Hydrochlorate, enanthate, caproate, hippurate, hydrochloride, hydrobromate, hydriodate, 2- isethionates, iodide, hydroxyl Esilate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, inclined phosphorus Hydrochlorate, mesylate, methyl benzoic acid salt, dibasic alkaliine, 2- naphthalene sulfonates, hydrochloride, nitrate, oxalates, oleate, Palmitate, pectate, persulfate, ALPHA Tolylic acid salt, 3- phenylpropionic acids salt, phosphate, phosphonate, phthalate, But it is not limited to this.
In addition, the alkali salt of the compound of the present invention includes aluminium, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc salt, but it is not limited to this.Above-mentioned salt is preferably ammonium, alkali metal salt sodium and potassium, and alkaline earth is golden Belong to salt calcium and magnesium.
The salt of the Formulas I a or Ib that are obtained by pharmaceutically acceptable organic nontoxic alkali compound includes primary, secondary and tertiary amine, Substitute amine, also include natively existing substitution amine, cyclic amine and deacidite (such as arginine, glycine betaine, Caffeine, chloroprocanine, choline, Ν, Ν '-dibenzyl-ethylenediamine (benzyl star (benzathine)), dicyclohexyl amine, diethanol Amine, diethylamine, 2- DEAE diethylaminoethanols, DMAE, monoethanolamine, ethylenediamine, N-ethylmorpholine, N- ethyl piperazines Pyridine, gucosamine, Glucosamine, histidine, Kazakhstan amine (hydrabamine), isopropylamine, lidocaine, lysine, Portugal's first Amine, N- methyl-D-glucarnines, morpholine, piperazine, piperidines, polyamino resin, procaine, purine, theobromine, triethanolamine, three Ethamine, trimethylamine, tripropyl amine (TPA) and three (hydroxymethyl) methylamines (tromethamine (tromethamine)), but be not limited to This.
Compound available reagent (such as (C of the invention containing Basic nitrogen-containing groups1-C4) alkyl halide, such as methyl, Ethyl, isopropyl and t butyl chloride, bromide and iodide；Two (C1-C4) alkyl sulfate, such as dimethyl, diethyl With diamyl sulfate；(C10-C18) alkyl halide, such as decyl, dodecyl, lauryl, myristyl and octadecyl Chloride, bromide and iodide；With aryl (C1-C4) alkyl halide, such as Methoxybenzyl chloride and phenylethyl bromide) season Ammonium.Such salt can be used to prepare for the water of the present invention-and oil-soluble compound.
Preferable above-mentioned pharmaceutical salts include acetate, trifluoroacetate, benzene sulfonate, citrate, fumarate, grape Sugar lime, hemisuccinic acid salt, hippurate, hydrochloride, hydrobromate, isethionate, mandelate, meglumine, nitrate, Oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thio apple Hydrochlorate, toluene fulfonate and trihydroxy methyl amine, but it is not limited to this.
Particularly preferred hydrochloride, dihydrochloride, hydrobromate, maleate, mesylate, phosphate, sulfate and amber Amber hydrochlorate.
The acid-addition salts of alkaline Formulas I a or Ib compound are prepared as follows：By by needed for free alkali form and sufficient amount Acid contact, so that forming salt in a usual manner.
Can be by the way that salt form be contacted with alkali and isolates free alkali in a usual manner to regenerate free alkali.With regard to some physics For property, its corresponding salt form is different in some aspects for free alkali form, such as the solubility side in polar solvent Face；However, for the purposes of the present invention, salt is suitable with its respective free alkali form in other side.
As described above, the pharmaceutically acceptable base addition salts of Formulas I a or Ib compound are by metal or amine (such as alkali metal With alkaline-earth metal or organic amine) formed.Preferable metal is sodium, potassium, magnesium and calcium.Preferable organic amine is Ν, Ν '-dibenzyl Ethylenediamine, chloroprocanine, choline, diethanol amine, ethylenediamine, N- methyl-D-glucarnines and procaine.
The base addition salts of the following acid compound for preparing the present invention：By by free acid form and the alkali needed for sufficient amount Contacted, so that forming salt in a usual manner.
Can be by the way that salt form be contacted with acid and isolates free acid in a usual manner to regenerate free acid.With regard to some physics For property, its corresponding salt form is different in some aspects for free acid form, such as the solubility side in polar solvent Face；However, for the purposes of the present invention, salt is suitable with its respective free acid form in other side.
If the compound of the present invention contains the group that more than one can form such pharmaceutically acceptable salt, Then the present invention also includes double salt.Typical Multiple salts forms include such as two tartrates, diacetate, two fumarates, two Portugals Methylamine, diphosphate, disodium salt and tri hydrochloride, but it is not limited to this.
On described above, it is seen that the statement " pharmaceutically acceptable salt " in this paper contexts refers to its salt 1 kind of form includes the active component of Formulas I a or Ib compound, if the particularly active component with free form or relatively early use Any other salt form of active component compare, the salt form assigns the improved pharmacokinetic property of active component.Activity The pharmaceutically acceptable salt form of composition can also provide desirable pharmacokinetic property for the active component first (should Active component is not having the pharmacokinetic property before this), and on its therapeutic efficiency in body possibly even There is actively impact to the pharmacodynamics of the active component.
Isotope
In addition, Formulas I a or Ib compound are intended to the form for including its isotope marks.In addition to following facts, Formulas I a's or Ib The form of the isotope marks of compound is equal with the compound：One or more atoms of the compound are by atom Quality or mass number one or more atoms different from the atomic mass or mass number of the atom common in nature replace Change.Be easy to commercially available and can be included by the example of the isotope in well-known method introduction-type I compound hydrogen, Carbon, nitrogen, oxygen, phosphorus, the isotope of fluorine and chlorine, such as be respectively2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F and36Cl.The Formulas I a or Ib of other isotopes containing one or more above-mentioned isotopes and/or other atoms compound, its prodrug Or its any pharmaceutically acceptable salt is intended to as the part of the present invention.The Formulas I a or Ib of isotope marks chemical combination Thing can by it is a variety of it is favourable in a manner of use.For example, the Formulas I a or Ib of isotope marks compound (have wherein for example been mixed and put Injectivity isotope is such as3H or14C) it is suitable for medicine and/or substrate tissue measure of spread.Because easily prepared and excellent is examined The property surveyed, these particularly preferred radio isotopes, i.e. tritium (3H) and carbon-14 (14C).In Formulas I a or Ib compound introduce compared with Isotope again (such as deuterium (2H)) there is treatment advantage, this higher generation for being attributed to the compound of the isotope marks thanks to stabilization Property.Higher generation thanks to stability and directly results in increased Half-life in vivo or lower dosage, and it will in most cases be represented The preferred embodiments of the invention.Generally, by carrying out in synthetic schemes and relevant description, in embodiment part and The operation prepared disclosed in part of text, the reactant of nonisotopic labels is replaced with the reactant for the isotope marks being easy to get, The Formulas I a or Ib of isotope marks compound can be prepared.
In order to by the oxidative metabolism of compound described in primary kinetic isotope effect control, can also by deuterium (2H) introduce In Formulas I a or Ib compound.The primary kinetic isotope effect is the chemical reaction as caused by the exchange of Isotopes The change of speed, the change again by after the isotope exchange covalent bond form the change of required Ground State Energy and cause.It is heavier The exchange of isotope typically results in the reduction of the Ground State Energy of chemical bond, therefore the rate reduction for being broken speed limit key.If key is broken Occur along the coordinate of more products reaction saddle point area or its near, then can significantly modify product distribution proportion.Such as：If deuterium with The not carbon atom bonding at its interchangeable sites, then kM/kD=2 ~ 7 speed difference is typical.If by the speed difference successfully Applied to the compound for the Formulas I a or Ib for being easy to oxidation, then property inside the compound can be significantly changed, and cause to change Kind pharmacokinetic property.
When finding and developing therapeutic agent, those skilled in the art attempt to optimize pharmacokinetic parameter, and keep simultaneously Desirable body outer property.Have reason to speculate, the compound that many has poor pharmacokinetic property is easy to oxidative metabolism.Mesh Preceding available external hepatomicrosome measure can provide the valuable information of the process on this kind of oxidative metabolism, described information Allow reasonable design by oxidative metabolism as confrontation and the Formulas I a or Ib of the deuterate with the stability improved change again Compound.Thus significantly improving for the pharmacokinetic property of Formulas I a or Ib compound is obtained, and can be quantified in the following manner Ground represents：Under concentration (Cmax), dose response curve when Half-life in vivo (t1/2), maximum hospital benefit area (AUC) with And F increase；And clearance rate, dosage and the material cost reduced.
Herein below is intended to explain the above：By multiple potential attack sites with oxidative metabolism (such as on benzyl Hydrogen atom and hydrogen atom with nitrogen atom bonding) Formulas I a or Ib compound be prepared as a series of analogs, wherein hydrogen is former Son various combination substituted by D-atom so that in these hydrogen atoms some, largely or entirely substituted by D-atom.Half The phase measure that declines can advantageously and accurately determine the improvement degree of improved oxidative metabolism resistance.In this way, determine The result exchanged as this kind of deuterium-hydrogen, half-life period of parent compound can extend for up to 100%.
Deuterium-hydrogen in Formulas I a or Ib compound, which exchanges, can also be used for realizing the metabolin for beneficially modifying initial compounds Spectrum, to reduce or eliminate undesirable toxic metabolite.If for example, carbon-hydrogen (C-H) key that toxic metabolite passes through oxidisability Cracking and produce, then can reasonably assume that, the analog of deuterate will greatly reduce or eliminate the generation of undesirable metabolin, In the case that specific oxidation is not rate-determining step.The other information of the prior art exchanged on deuterium-hydrogen can be found in Such as Hanzlik et al., J. Org. Chem. 55,3992-3997,1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987、Foster, Adv. Drug Res. 14, 1-40, 1985、Gillette et Al, Biochemistry 33 (10) 2927-2937,1994 and Jarman et al. Carcinogenesis 16 (4), 683-688, 1993。
In addition, the present invention relates to medicine, it is included：At least one kind of Formulas I a or Ib compound and/or its is pharmaceutically acceptable Salt, dynamic isomer and stereoisomer, include the mixture of its all proportions；With arbitrary excipient and/or assistant agent.
The dosage unit form for the active component that pharmaceutical preparation can include scheduled volume with every dosage unit is administered.Such list Position can include such as 0.5mg ~ 1g, preferably 1mg ~ 700mg, particularly preferred 5mg ~ 100mg compound of the invention, and this is depended on Age, body weight and the situation of the illness, medication and the patient that are treated, or pharmaceutical preparation can be included in advance with every dosage unit The dosage unit form administration of quantitative active component.Preferable dosage unit preparations be comprising daily dosage as noted above or Those of the appropriate section of Fractional or active component.
In addition, this kind of pharmaceutical preparation can use the commonly known method of pharmaceutical field to prepare.
Pharmaceutical preparation is applicable to be administered via any required proper method, such as oral (including buccal or sublingual), Rectum, nose, part (including buccal, sublingual or transdermal), vagina or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) Method.All methods known to pharmaceutical field can be used to prepare for such preparation, for example, by by active component and excipient or Assistant agent mixes.
Pharmaceutical preparation suitable for oral administration can be administered as individual, the individual be, for example, capsule or Tablet, powder or granule, solution or supensoid agent in water-based or non-aqueous liquid, edible foam or foam food Thing, or oil-in-water liq emulsion or water-in-oil liquid emulsion.
Thus, for example in the case where being administered orally in the form of a tablet or capsule, can by active ingredient components with it is oral Nontoxic and pharmaceutically acceptable inert excipient (such as ethanol, glycerine, water) merges.Powder agent is by the way that compound is crushed To appropriate thin size and by itself and pharmaceutical excipient (such as edible carbohydrate (such as starch that crushes in a similar manner Or mannitol)) mix to prepare.Also flavouring, preservative, dispersant and dyestuff may be present.
By preparing mixture of powders as described above and being filled into the gelatin shell of shaping, capsule is prepared.Filled out Before filling operation, can be added in mixture of powders glidant and lubricant (silicic acid of such as high degree of dispersion, talcum powder, magnesium stearate, The polyethylene glycol of calcium stearate or solid form).Also can add disintegrant or solubilizer (such as agar, calcium carbonate or sodium carbonate) with Improve the availability of the medicine after capsule is taken.
In addition, if desired or necessary, then can also mix in the mixture suitable adhesive, lubricant and disintegrant and Dyestuff.Suitable adhesive include starch, gelatin, natural carbohydrate (such as glucose or beta lactose), the sweetener as made from corn, Natural and synthetic rubber (such as Arabic gum, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax).These The lubricant used in formulation includes enuatrol, odium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc..Disintegration Agent includes starch, methylcellulose, agar, bentonite, xanthans etc. without limitation.Prepare tablet as follows：Such as prepare powder Last mixture, by the granulating mixture or dry-pressing, add lubricant and disintegrant and whole mixture is pressed into tablet.Passing through will The compound crushed in a suitable manner mixes with above-mentioned diluent or matrix, and optionally with adhesive (such as carboxymethyl cellulose, Alginate, gelatin or polyvinylpyrrolidone), dissolution retarding agent (such as paraffin), sorbefacient (such as quaternary salt) and/or absorb Agent (such as bentonite, kaolin or Dicalcium Phosphate) mixes, and prepares mixture of powders.Can be by using adhesive (such as syrup, starch Paste, Arabic gum rubber cement or the solution-wet of cellulose or polymeric material, and sieved and mixture of powders is pelletized. As a kind of alternative of granulation, mixture of powders can be made to obtain the uneven block of shape by tablet press machine, be broken It is broken so as to forming particle., can be by particle lubrication, to prevent from adhering to by adding stearic acid, stearate, talcum powder or mineral oil On tablet mold.Then, the mixture of lubrication is pressed into tablet.Also can be by the compound of the present invention and the inertia of free-flowing Excipient merges, and is then directly pressed into tablet without granulation or dry compressing step.It may be present by shellac sealant, sugar or polymerization The transparent or opaque protective layer of the gloss layer of thing material layer and wax composition.Dyestuff can be added in these coating agents so as to energy Distinguish different dosage units.
It is pre- so that specified rate includes that liquid oral (such as solution, syrup and elixir) can be prepared to dosage unit form Quantitative compound.Syrup can be by the way that compound be dissolved in the aqueous solution with suitable flavouring to prepare, and the wine made of broomcorn millet Agent is prepared with nontoxic alcohol carrier.Supensoid agent can be by the way that compound be scattered in non-toxic carrier to prepare.Also can add Solubilizer and emulsifying agent (isooctadecanol and polyoxyethylene sorbitol ethers of such as ethoxylation), preservative, flavoring additive are (such as Peppermint oil or natural sweetener or saccharin or other artificial sweetening agents etc.).
If desired, then the dosage unit preparations for oral administration can be encapsulated in micro-capsule.It can also discharge and be extended Or the mode of delay carrys out preparation of preparation, such as by the way that microparticle material to be coated or embedded to be prepared with polymer, wax etc. Agent.
Formulas I a or Ib compound and its pharmaceutically acceptable salt, dynamic isomer and stereoisomer can also lipids The form of body delivery system (such as small monolayer vesicle, big monolayer vesicle and multi-layer vesicles) is administered.Can be from various phosphatide (such as courages Sterol, stearylamine or phosphatidyl choline) form liposome.
Formulas I a or Ib compound and its pharmaceutically acceptable salt, dynamic isomer and physiological feature derive Thing can also deliver by the use of monoclonal antibody as separate carrier, wherein the compound molecule is coupled with the monoclonal antibody. Compound can be coupled on the soluble polymer as target medicine carrier.Such polymer may include polyvinyl pyrrole Alkanone, pyran co-polymer, poly- hydroxypropylmethacrylamide base phenol, poly- hydroxyethyl asparaginyl group phenol or polyoxygenated Ethene polylysine, it is substituted by palmityl.Compound can be also coupled to a kind of biology for being adapted for carrying out medicine controlled releasing can On degradation polymer, such as PLA, poly- 6-caprolactone, poly butyric, poe class, polyacetals, poly- dihydroxy pyrrole Mutter class, the crosslinking of polybutylcyanoacrylate class and hydrogel or amphipathic nature block polymer.
Be adapted to percutaneous dosing pharmaceutical preparation can as the independent emplastrum that the epidermis with recipient is in close contact extensively to Medicine.Therefore, such as Pharmaceutical Research, 3 (6), described in the generic term in 318 (1986), for example (,) it is available Ionotherapy makes active component be delivered from emplastrum.
The medicinal compound for being adapted to locally be administered can be formulated into ointment, cream, supensoid agent, lotion, powder, solution Agent, paste, gel, spray, aerosol or oil.
Treatment for eye or other outside organizations (such as mouth and skin), preparation is preferably with topical ointment agent or breast The form application of paste., can be by the miscible emulsifiable paste matrix of active component and paraffin or water in the case where being configured to ointment Apply together.Alternatively, active component can be configured to cream with oil-in-water type emulsifiable paste matrix or water-in-oil base.
Be adapted to the pharmaceutical preparation for being applied topically to eye to include eye drops, wherein by active component dissolve or be suspended in it is suitable In carrier, particularly aqueous solvent.
It is adapted to the pharmaceutical preparation of the topical application in mouth to include tablet, film agent and collutory.
It is adapted to the pharmaceutical preparation of rectally can be administered in the form of suppository or enema.
Wherein carrier mass is that the pharmaceutical preparation of the suitable nasal administration of solid is included with for example in 20-500 micrometer ranges The corase meal of interior granularity, it is administered in a manner of being sucked from nose, i.e., rapid containing powder container from close nose via nasal meatus Suction.Include by the use of liquid as carrier mass, as the suitable formulations that nasal spray or nasal drop are administered active component in water or Solution in oil.
Fitting through the pharmaceutical preparation of inhalation includes fine particles powder or mist, and the fine particles powder or mist can be by various Pressurization distributor, sprayer or the insufflator containing aerosol of type produces.
It is adapted to the pharmaceutical preparation of vagina administration can be used as vaginal plug, tampon, cream, gel, paste, foam or spray Mist preparation is administered.
It is adapted to the pharmaceutical preparation of parenteral to include：Water-based and non-aqueous aseptic injectable solution agent, it includes antioxygen Agent, buffer, bacteriostatic agent and solute, cause that preparation and the blood for the recipient to be treated are isotonic whereby；It is and water-based and non- Water-based sterile suspensions, it can include suspension medium and thickener.Preparation (such as can seal in single dose or multi-dose container Ampoule and bottle) in be administered, and be freeze-dried (lyophilized) state storage so that only need to before use addition sterile carrier liquid Body (such as water for injection).The injection solution and supensoid agent prepared according to prescription can be from aseptic powdery agent, granule and tablet Prepare.
Self-evident, more than in addition to specifically mentioned component, preparation can be also included for the particular type preparation at this The other reagents commonly used in field；Thus, for example the preparation for being adapted to be administered orally can include flavouring.
The therapeutically effective amount of Formulas I a or Ib compound depends on many factors, including the age of such as animal and body weight, Need the precise condition and its order of severity, the property of the preparation and medication treated, and finally by the doctor in charge or animal doctor Lai Determine.But the effective dose of compound of the invention is typically in 0.1 ~ 100mg/kg recipients (mammal) body weight/day In the range of, especially it is that typically in the range of 1 ~ 10mg/kg body weight/days.Therefore, the Adult Mammals for body weight for 70kg For, daily actual amount is generally between 70 ~ 700mg, and wherein the amount can be as daily single dose administration, or generally It is administered in a series of daily broken doses (such as 2,3,4,5 or 6 parts) so that total daily dose is identical.Can be by its salt or molten The effective dose of agent compound or the effective dose of physiological functional derivatives are defined as compound effective of the present invention in itself The part of amount.It can be assumed that comparable amount is applied to treat above-mentioned other illnesss.
This kind of combined therapy can be realized by means of simultaneously, continuously or respectively distributing each component of the treatment.This kind of combination Product uses compound of the invention.
In addition, the present invention relates to medicine, it is included：At least one kind of Formulas I a or Ib compound and/or its is pharmaceutically acceptable Salt, dynamic isomer and stereoisomer, include the mixture of its all proportions；With at least one kind of other pharmaceutical activity into Point.
The invention further relates to the external member (kit) being made up of following independent bag：
(a) the Formulas I a of effective dose or Ib compound and/or its pharmaceutically acceptable salt, dynamic isomer and alloisomerism Body, include the mixture of its all proportions；With
(b) the other active constituents of medicine of effective dose.
The external member includes suitable container, such as box, single bottle, bag or ampoule.The external member can include for example single ampoule, Each ampoule each the Formulas I a comprising effective dose or Ib compound and/or its pharmaceutically acceptable salt, solvate and vertical Body isomers, include the mixture of its all proportions,
With effective dose in dissolving or the other active constituents of medicine of lyophilized form.
" treatment " used herein refers to the symptom that upper alleviation is related to illness or disease in whole or in part, or slows down or stop The only further progress of those symptoms or deterioration, or prevent or prevent the disease of the subject with development disease or illness risk Disease or illness.
The term " effective dose " relevant with Formulas I a or Ib compound can refer to such amount, and it can alleviate in whole or in part The symptom related to illness or disease, the further progress of those symptoms is either slowed or stopped or deterioration or prevents or in advance The disease or illness of the anti-subject with disease disclosed herein or with the risk for developing the disease, the disease or Illness such as inflammatory conditions, immune disorders, cancer or metabolic disorder.
In 1 embodiment, the effective dose of Formulas I a or Ib compound is for example to suppress intracellular in vitro or in vivo PDHK amount.In some embodiments, compared with the PDHK activity in untreated cell, the Formulas I a or Ib of effective dose change Compound suppresses intracellular PDHK up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%.Formulas I a or Ib chemical combination The effective dose (such as in pharmaceutical composition) of thing can be the level of effect needed for generation；For example, for oral and parenteral outer Administration is for both, the about 10mg/kg subject's body weight of 0.005mg/kg subject's body weight ~ about in unit dose.
Purposes
Present invention relates particularly to Formulas I a or Ib compound and its pharmaceutically acceptable salt, dynamic isomer and alloisomerism Body, include the mixture of its all proportions, it is used for the purposes for the treatment of cancer, diabetes and heart ischemia.
In addition, the present invention relates to Formulas I a or Ib compound and its pharmaceutically acceptable salt, dynamic isomer and solid Isomers, include the mixture of its all proportions, its be used to treating insulin resistance syndrome, metabolic syndrome, hyperglycemia, Dyslipidemia, atherosclerosis, heart failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondriopathy, mitochondria brain flesh The purposes of disease.
Present invention relates particularly to for treating or preventing cancer, diabetes and the method for heart ischemia, it includes will be effective The Formulas I a or Ib compound or its pharmaceutically acceptable salt, dynamic isomer, stereoisomer or solvate of amount are to having This snibject needed.
Also Formulas I a or Ib compound and/or its pharmaceutically acceptable salt, dynamic isomer and stereoisomer are included For preparing the purposes of medicine, the disease for the PDHK inductions that the medicine is used to treat or prevent in mammal or PDHK inductions Illness, according to methods described, the compound of the invention of therapeutically effective amount is moved to the ill lactation treated as needs Thing is administered.The therapeutic dose changes according to disease specific, and those skilled in the art are without excessively making great efforts to can determine that.
Statement " disease or illness of PDHK inductions " refers to the active pathological conditions depending on PDHK.Have with PDHK activity The disease of pass includes cancer, diabetes and heart ischemia.
Present invention relates particularly to Formulas I a or Ib compound and its pharmaceutically acceptable salt, dynamic isomer and solid are different Structure body, include the mixture of its all proportions, it is used to treat the disease that PDHK suppression, regulation and/or regulation and control suppress to work The purposes of disease.
Present invention relates particularly to Formulas I a or Ib compound and its pharmaceutically acceptable salt, dynamic isomer and solid are different Structure body, include the mixture of its all proportions, it is used for the purposes for suppressing PDHK.
The representative cancer that Formulas I a or Ib compound can be used for treating or preventing includes but is not limited to：Head, neck, eye, mouth, Throat, oesophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovum Nest, testis or other reproductive organs, skin, thyroid gland, blood, lymph node, kidney, liver, pancreas, brain, the cancer of central nervous system Disease, solid tumor and blood-born tumor (blood-borne tumor).
In addition, the representative cancer that Formulas I a or Ib compound can be used for treating or preventing includes the cancer (colloid of brain Knurl), spongioblastoma, leukaemia, Bannayan-Zonana syndromes, cowden's disease, Lhermitte-Duclos disease, breast Cancer, Inflammatory breast cancer, the nephroblastoma, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, Kidney, lung cancer, liver cancer, melanoma, oophoroma, cancer of pancreas, prostate cancer, sarcoma, osteosarcoma, bone and thyroid giant cell Knurl.
It is preferred that the present invention relates to the method that disease is cancer.
Particularly preferably the present invention relates to the method that disease is cancer, wherein, administration is and at least one kind of other active medicines Reagent simultaneously, pass through sequence or alternating delivery.
Disclosed Formulas I a or Ib compound can include anti-with other known therapeutic agent combination medicine-feeding, the therapeutic agent Cancer medicine.Terminology used herein " anticarcinogen " is related to treating cancer and any medicament to being administered to the patient with cancer.
Anticancer therapy defined above can be used as monotherapy application, or the compound except Formulas I a or Ib disclosed herein In addition, routine operation or radiotherapy or drug therapy be may also include.Such drug therapy (such as chemotherapy or targeting are controlled Treat) it may include one or more, it is preferred that a kind of following antitumor agent：
Alkylating agent
As hemel, bendamustine, busulfan, BCNU, Chlorambucil, mustargen, endoxan, Dacarbazine, Ifosfamide, Improsulfan, toluene fulfonate, lomustine, melphalan, dibromannitol, mitolactol, Ni Mosi Spit of fland, Ranimustine, Temozolomide, phosphinothioylidynetrisaziridine, Treosulfan, nitrobin, carboquone；
A Paqi quinones, Fotemustine, glufosfamide, Pa Li cut down rice, pipobroman, Trofosfamide, uracil mustard, TH-3024、 VAL-0834；
Platinum compounds
Such as carboplatin, cis-platinum, eptaplatin, Miboplatin hydrate, oxaliplatin, lobaplatin, Nedaplatin, JM473, Satraplatin；
Lobaplatin, Nedaplatin, JM473, Satraplatin；
DNA changes agent
Such as Amrubicin, bisantrene, Decitabine, mitoxantrone, procarbazine, ET-743, clofarabine；
His sharp star, pixantrone, La Luomositing of SN-11841, bromine1,3；
Topoisomerase enzyme inhibitor
Such as Etoposide, Irinotecan, razoxane, Sobuzoxane, Teniposide, Hycamtin；
Amonafide, Belotecan, Elliptinium Acetate, AG-7352；
Micro-pipe dressing agent
As Cabazitaxel, Docetaxel, eribulin, Ipsapirone, taxol, vincaleukoblastinum, vincristine, vinorelbine, Eldisine, vinflunine；
Fu Tabulin, tesetaxel；
Antimetabolite
Such as asparaginase3, azacitidine, Calcium Levofolinate, capecitabine, Cladribine, cytarabine, enocitabine, fluorine Uridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate (MTX), nelarabine, pemetrexed, Pralatrexate, sulphur azoles Purine, thioguanine, Carmofur；
Doxifluridine, Ai Xi Rabins, Raltitrexed, 1-(2-C-cyano-2-dioxy-BETA-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine, Tegafur2,3, Trimetrexate；
Antitumor antibiotic
As bleomycin, actinomycin D, Doxorubicin, epirubicin, idarubicin, levamisol, Miltefosine, mitogen are mould Plain C, romidepsin, streptozotocin, valrubicin, Zinostatin, zorubicin, daunorubicin, plicamycin；
Aclarubicin, Peplomycin, THP；
Hormone/antagonist
As abarelix, abiraterone, Bicalutamide, Buserelin, Calusterone, Chlorotrianisene, Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2, fill in rice Pine, estradiol, fluocortolone, Fluoxymesterone, Flutamide, fulvestrant, Goserelin, Histrelin, Leuprorelin, first it is pregnant Ketone, mitotane, nafarelin, nandrolone, Nilutamide, Octreotide, prednisolone, Raloxifene, TAM, thyroid-stimulating hormone α, Toremifene, Trilostane, Triptorelin, diethylstilbestrol；
Acolbifene, DANAZOL, Deslorelin, epithioandrostanol, orteronel, En Zhalu amine1,3；
Aromatase inhibitor
Such as aminoglutethimide, Anastrozole, Exemestane, Fadrozole, Letrozole, Testolactone；
Formestane；
Small molecule kinase inhibitors
If gram azoles is for Buddhist nun, Dasatinib, Tarceva, Imatinib, Lapatinib, AMN107, pazopanib, Rui Gefei Buddhist nun, Luso are for Buddhist nun, Sorafenib, Sutent, Fan Tanibu, Wei Luofeini, SKI-606, Gefitinib, pazopanib；
Afatinib, alisertib, dabrafenib, up to gram for Buddhist nun, dinaciclib, degree dimension for Buddhist nun, Enzastaurin, Ni Dani Cloth, it is happy cut down for Buddhist nun, linifanib, linsitinib, Masitinib, midostaurin, for husky Buddhist nun, HKI-272, Orantinib, perifosine, moor that for Buddhist nun, thunder more for Buddhist nun, rigosertib, Zarnestra, tivantinib, Tivozanib, Sibutramine Hydrochloride replace Buddhist nun for Buddhist nun, pimasertib, alanine Bu Linibu, AZD2171, Ah pa4, S- malic acid cards win For Buddhist nun1,3, according to Shandong replace Buddhist nun1,3, Conmana4、buparlisib2、cipatinib4, examine than for Buddhist nun1,3, Chinese mugwort for Larry this1,3、 fedratinib1、XL-6474；
Sensitising agent
Such as Methoxsalen3；
Porfimer Sodium, talaporfin, Temoporfin；
Antibody
As alemtuzumab, shellfish rope monoclonal antibody, Brentuximab vedotin, Cetuximab, Shu Dankang, her wooden monoclonal antibody, Austria Method wood monoclonal antibody, pa wood monoclonal antibody, Rituximab, tositumomab, trastuzumab, bevacizumab, the appropriate monoclonal antibody of training2,3；
Catumaxomab, according to Lip river pearl monoclonal antibody, epratuzumab, method profit pearl monoclonal antibody, mogamulizumab, how former times wood monoclonal antibody, Buddhist nun are appropriate Pearl monoclonal antibody, Ah's Torr pearl monoclonal antibody, ocaratuzumab, Ao Gefu monoclonal antibody, thunder not Lu Dankang, the appropriate wooden monoclonal antibody of profit, the appropriate former times monoclonal antibody of department, support Pearl monoclonal antibody, prick calamite monoclonal antibody, prick wooden monoclonal antibody, matuzumab, dalotuzumab1,2,3、onartuzumab1,3, thunder it is appropriate not single It is anti-1、tabalumab1,3、EMD-5257974、nivolumab1,3；
Cell factor
Such as Aldesleukin, interferon-' alpha '2, Interferon a2a3, interferon alpha 2 b2,3；
Celmoleukin, Ta Suonaming, Teceleukin, oprelvekin1,3, recombinant interferon β -1a4；
Drug conjugate
Such as denileukin, ibritumomab tiuxetan, MIBG I123, prednimustine, trastuzumab-emtansine (trastuzumab emtansine), Estramustine, gemtuzumab, ozogamicin, VEGF Trap；
The pungent interleukin of shellfish, according to peptide of writing music, Yi Zhu monoclonal antibodies ozogamicin, Ta Namo monoclonal antibodies, pearl monoclonal antibody not difficult to understand, technetium (99mTc) A Xi Not monoclonal antibody1,3、vintafolide1,3；
Vaccine
Such as sipuleucel3；vitespen3、emepepimut-S3、oncoVAX4、rindopepimut3、troVax4、MGN- 16014、MGN-17034；
It is other
Alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, Methyltyrosine, meter Fa Mo peptides, Pamidronic Acid, Pegaspargase, Pentostatin, sipuleucel3, it is sizofiran, Tamibarotene, smooth Luo Mosi, Thalidomide, Tretinoin, vismodegib, zoledronic acid, SAHA；
Celecoxib, cilengitide, entinostat, etanidazole, ganetespib, she bend promise former times, iniparib, Ixazomib, Lonidamine, Nimorazole, LBH589, Pelretin acid, Puli's peptide are new, pomalidomide, procodazole, phosphorus not Moral, telotristat, thymalfasin, Tirapazamine, support takes charge of him, bent Bei Desheng, ubenimex, cuts down department Piao for department, his quinoline Reach, Gendicine4, molten chain bacterium4、reolysin4, IPI-5041,3、trebananib2,3, virulizin4, Ka Feizuo Rice1,3, endostatin4、immucothel4, Belling department he3、MGN-17034；
1Prop. INN (the international nonproprietary name of proposal)
2Rec. INN (the international nonproprietary name of recommendation)
3USAN (title that the U.S. uses)
4Without INN.
Abridge below and refer to definition hereafter respectively：
Aq (water-based), h (hour), g (gram), L (liter), mg (milligram), MHz (megahertz), min. (minute), mm (millimeter), mmol (mM), mM (mM), m.p. (fusing point), eq (equivalent), mL (milliliter), μ L (microlitre), ACN (acetonitrile), AcOH (acetic acid), CDCl3(Deuterated chloroform), CD3OD (deuterated methanol), CH3CN (acetonitrile), c-hex (hexamethylene), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane), DIC (Diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide (DMSO)), DMSO-d6(deuterate dimethyl Sulfoxide), EDC (1- (3- dimethyl-amino-propyls) -3- ethylcarbodiimines), ESI (electrospray ionization), EtOAc (ethyl acetate), Et2O (ether), EtOH (ethanol), HATU (dimethylaminos-([1,2,3] triazol [4,5-b] pyrrole Pyridine -3- bases epoxide)-methylene]-dimethyl-ammonium hexafluorophosphate), HPLC (high performance liquid chromatography), i-PrOH (2- third Alcohol), K2CO3(potassium carbonate), LC (liquid chromatography), MeOH (methanol), MgSO4(magnesium sulfate), MS (mass spectrography), MTBE (methyl tertiary butyl ether), NaHCO3(sodium acid carbonate), NaBH4(sodium borohydride), NMM (N-methylmorpholine), (nuclear-magnetism is common by NMR Shake), PyBOP (BTA -1- base-epoxides-three-pyrrolidinyl-phosphonium hexafluorophosphate), RT (room temperature), Rt is (during reservation Between), SPE (SPE), TBTU (2- (1-H- BTA -1- bases) -1,1,3,3- tetramethylureas tetrafluoroborate), TEA (triethylamine), TFA (trifluoracetic acid), THF (tetrahydrofuran), TLC (thin-layered chromatography), UV (ultraviolet).
The description of vitro assay
Abbreviation：
GST=glutathione-S-transferase
FRET=FRET
HTRF=(homogeneous phase time discrimination fluorescence)
HEPES=4- (2- hydroxyethyls) -1- piperazine ethanesulfonic acid buffers
DTT=dithiothreitol (DTT)
BSA=bovine serum albumin(BSA)
CHAPS=3- [(3- courages amido propyl) dimethylamino] -1- propane sulfonic acid inner salts.
PDHK2 life chemistry active testing：PDC Deactivations
Biochemical activity for PDHK2 analyzes the inactivation based on the PDC caused by PDHK2 phosphorylation.The analysis is with 2 Step is carried out：Enzyme PDHK2 reacts, wherein the PDC separated by the use of ATP as cosubstrate by PDHK2 phosphorylations；Lived with PDC Property analysis, wherein pyruvic acid and NAD are converted into acetylcoenzyme and NADH.PDC activity is relevant with NADH increase, thus can be straight Increased fluorescence signal (Exc 340nm, Em 450nm) was connected to be measured.PDHK2 suppression causes relatively low phosphorylation State, thus less reduce PDC activity and more strongly increase NADH fluorescence signals.
PDC Deactivations are carried out in the hole microwell plates of Greiner 384, for high flux screening.At room temperature, testing Under the absence or presence of compound (10 diluted concentrations), in kinase buffer agent (15mM potassium phosphate buffer agents, pH 7.0,60mM KCl, 1.5mM DTT, 2.5mM MgCl2, 0.0125% (w/v) BSA, 0.125% pluronic F-68) in by 4 μ L PDHK2 (people, rec, Carna Bioscience, 10ng/ μ L ~ 137nM final concentration) (separates, Sigma- with PDC from Pigs Hearts Aldrich, 20mU/mL final concentration) it is incubated 30min.By adding 4 μ L ATP substrate solutions, (fc in kinase buffer agent is 5 μ Μ) trigger kinase reaction.After 37 DEG C are incubated 30min, 40 μ L PDC reaction solutions (100mM Tris/HCI, pH are added 7.8,0.5mM EDTA, 1mM MgCl2, 50mM NaF, 0.25mM coacetylases, 5mM pyruvic acid, 1mM NAD, 5mM DTT, 1mM are burnt Phosphoric acid sulphur ammonium).The 1st fluorescence measurement is carried out on Perkin Elmer Envision (Exc 340nm, Em 450nm).In room Reaction is incubated 45min under temperature.Then the 2nd fluorescence measurement is carried out, passes through the mathematic interpolation PDC activity of 2 measurements.As for The integrity value of PDHK2 analyses, reacted using the PDHK2 of no inhibitor.The null value pharmacologically used is final concentration of 3mM DCA (Sigma-Aldrich).Use program Symyx the Assay Explorer or Condosseo purchased from GeneData Determine inhibiting value (IC50).
Identical titration calorimetry
With VP-ITC micro calorimeters (Microcal, LLC/GE Healthcare Bio-Sciences AB, Uppsala, Sweden ITC measure) is carried out.Albumen (50 μ Μ) is titrated in test compound (5 μ Μ) to enter by using 12 μ L syringes The general titration of row.All Binding experiments are in 30 DEG C of progress.It is diluted to generally by test compound from DMSO mother liquors maximum dense eventually Spend in the measurement buffer for 1% DMSO.Measurement buffer is 20mM HEPES, 135mM KCl, 1mM TCEP, 2mM MgCl2、15mM NaH2PO4, pH 7.5.People PDHK2 (12-407) is prepared in Escherichia coli as histidine tagged protein, Purified by affinity chromatography.Removed and marked by side chain specific proteolysis (side specific proteolysis). Before titration, protein buffer agent is replaced by the measurement buffer for containing identical DMSO concentration as test compound diluent. ITC data analysis is carried out using the calorimetric softwares of Origin 7 for coming from same provider.For most of measurements, it is assumed that 1 The binding model of binding site., can calculations incorporated constant (K according to the mathematical modeling of applicationA), observation combination enthalpy (△ HOBS) And the stoichiometry (N) of the compound formed.In analysis above, due to the heat of dilution, by full from titration end-point Extrapolated with value to correct initial data.In order to directly be compared between corresponding experimentalists and technicians and protein formulation, pass through Protein concentration is corrected with reference to the titration of general Standard inhibitors.Apparent stoichiometric number defines binding active proteins matter The fraction of (binding competent protein), and the relative error in protein concentration measurement is compensated.The school Positive protein concentration is used to establish ITC experimentalists and technicians with test compound.Herein it was observed that with ideal 1:1 stoichiometry Any deviation is all attributed to the error of compound concentration.The nominal compound concentration is corrected, to realize 1 in being fitted:1 chemistry meter Amount.
For determining the cell analysis of compound activity
Compound activity is determined in cellular immunofluorescence measure.People's HEK293T cells are seeded to the black of clear bottom In the orifice plate of color 384, a night is cultivated.
Second day, test compound is added in hole, plate is incubated 5h.Then, cell is fixed with formaldehyde, permeated, envelope Close.First antibody Anti-PDH-E1 alpha (pSer300), AP1064 (Merck Millipore) are added, in plate hole It is incubated a night.Then, cell is washed, secondary antibody is together added with Hoechst 33258 (H3569, Invitrogen) Alexa Fluor 488, goat anti-rabbit ab (A-11008, Invitrogen), are incubated 1h in plate hole.Most Afterwards, cell is washed, plate is measured on Laser Scanning Cytometer acumen hci (TTpLabtech).
Initial data is standardized with reference to pharmacological inhibitor control, uses software kit Genedata screener (Genedata) by mapping percentage efficiency value to generate dose response curve.
Within a context, all temperature represent with DEG C.In the examples below, " conventional post processing " refers to：If desired then Add water, it is the value between 2 to 10 if desired then to adjust pH, according to the composition of final product, by mixture ethyl acetate or Dichloromethane extracts, and separates each phase, dries organic phase with sodium sulphate, evaporation, passes through silica gel chromatography and/or crystallization purifying.
LC/MS：
HPLC- methods：
Gradient：3.3min；Flow velocity：The B of 2.4mL/min, 4% B from 0min, 2.8min 100% B, 3.3min 100%
A：Water+HCOOH (0.05%Vol.)；B：Acetonitrile+HCOOH (0.04%Vol.)
Chromatographic column：Chromolith SpeedROD RP 18e 50-4.6
Wavelength：220nm
Agilent devices.
1H NMR are recorded in Bruker DPX-300, DRX-400, AVII-400 or BRUKER 500MHz spectroscopic measurements On instrument, internal standard is used as using the residual signal of deuterated solvent.Chemical shift (δ) with relative to residual solvent signal (δ= 2.49ppm1H NMR, DMSO-d6) ppm report.1H NMR datas are reported as follows：Chemical shift (multiplicity, coupling constant and Hydrogen number).Multiplicity abbreviation is as follows：S (unimodal), d (bimodal), t (triplet), q (quartet), m (multiplet), br (broad peak).
Embodiment
For the general reaction scheme of formula Ia compound, in Formulas I a, X=N, Y=CH.
Embodiment 1：
(2R) -1- [1- (4- chlorphenyls) -6,7- dihydro -4H- pyrazolos [4,3-c] pyridine -5- bases] fluoro- 2- hydroxyls of -3,3,3- three Base -2- methyl-propan -1- ketone (" A1 ")
1.1 1- (the chloro- phenyl of 4-) -1,4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- t-butyl formates
By 3- [1- dimethylaminos -methyl- (E)-subunit] -4- oxo piperidine -1- t-butyl formates (200mg, 0.786mmol) It is suspended in 4- chlorphenyls hydrazine hydrochloride (155mg, 0.865mmol) in methanol (4mL) and water (1mL).While stirring, add Enter glacial acetic acid (0.23mL, 3.932mmol), orange solution is formed after several minutes.1h is stirred the mixture at room temperature, uses acetic acid Ethyl ester dilutes, with water, the NaHCO of saturation3Solution and salt water washing, use Na2SO4Dry, filter and be evaporated to dryness.By quick Chromatography (Companion RF, 40g Si50 silica gel chromatographic columns) purifies oily residue.Yield：145.5mg brown oil； LC/MS, Rt：2.61min；(M+H) 334.1.
1.2 1- (the chloro- phenyl of 4-) -4,5,6,7- tetrahydrochysene -1H- pyrazolos [4,3-c] pyridine dihydrochloride
Compound 1.1 (145.5mg, 0.436mmol) is dissolved in the dry dioxane of Isosorbide-5-Nitrae-(3mL), adds chlorine at room temperature Change hydrogen (4M dioxane solutions, 4mL).After a few minutes, Light brown solid is separated out.Reactant mixture is stirred into 2h at room temperature, Diluted with ether (7mL), stir 5min.Precipitated by being filtered by suction, washed with ether, be dried at room temperature for 2h.Yield： 155mg yellow solids；LC/MS, Rt：1.16min；(M+H) 234.1.
1.3 (2R) -1- [1- (4- chlorphenyls) -6,7- dihydro -4H- pyrazolos [4,3-c] pyridine -5- bases] -3,3,3- three Fluoro- 2- hydroxy-2-methyls-propane -1- ketone
By compound 1.2 (155mg, 0.505mmol), (R) -3,3,3- tri- fluoro- 2- hydroxy-2-methyls-propionic acid (159mg, 1.006mmol) and [dimethylamino-([1,2,3] triazol [4,5-b] pyridin-3-yl epoxide)-methylene]-dimethyl-six Fluorophosphoric acid ammonium (383mg, 1.007mmol) is dissolved in DMF (2.5mL).Addition N- ethyl diisopropylamines (0.857mL, 5.037mmol), yellow solution is stirred overnight at room temperature.Reactant mixture is diluted with water (40mL), extracted with ethyl acetate Take.By the NaHCO of the organic layer saturation of merging3Solution and salt water washing, use Na2SO4Dry, filter and be evaporated to dryness.Pass through Flash chromatography (Companion RF, 24g Si50 silica gel chromatographic columns) purifies residue, then passes through preparative HPLC (Agilent 1260, chromatographic column：Waters SunFire C18,5 μm, 30 × 150mm) purifying residue.By containing for collection The fraction of product merges, and flashes to aqueous residue.With the NaHCO of saturation3The aqueous residue is adjusted to alkalescence by solution, uses acetic acid Ethyl ester extracts.By the organic layer of merging salt water washing, Na is used2SO4Dry, filter and be evaporated to dryness, residue is freezed.
Yield：114mg (60%) buff powder；LC/MS, Rt：2.19min；(M+H) 374.1；1H NMR (500MHz, DMSO-d6) δ 7.66-7.51 (m, 5H), 7.19 (s, 1H), 5.14-4.84 (m, 1H), 4.65- 4.47 (m, 1H), 4.23-3.96 (m, 1H), 3.90-3.64 (m, 1H), 3.04-2.80 (m, 2H), 1.66- 1.46 (m, 3H)。
Embodiment 2：
(2R) -1- [2- (4- chlorphenyls) -6,7- dihydro -4H- pyrazolos [4,3-c] pyridine -5- bases] fluoro- 2- hydroxyls of -3,3,3- three Base -2- methyl-propan -1- ketone (" A2 ")
Pass through preparative HPLC (Agilent 1260, chromatographic column in step 1.3：Waters SunFire C18, 5μm, 30 × 150mm) " A2 " of the separation as the isomerism cyclisation product of step 1.1.Yield：7mg (4%) colourless powder；LC/ MS, Rt：2.26min；(M+H) 374.1；1H NMR (500MHz, DMSO-d6) δ 8.33 (s, 1H), 7.82-7.76 (m, 2H), 7.55-7.50 (m, 2H), 7.21 (s, 1H), 5.16-4.94 (m, 1H), 4.69-4.50 (m, 1H), 4.28-4.02 (m, 1H), 3.94-3.68 (m, 1H), 2.93-2.68 (m, 2H), 1.66-1.45 (m, 3H)。
Embodiment 3：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three (1- phenyl -1,4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- Base)-propane -1- ketone (" A3 ")
Prepared as embodiment 1 (step 1.1 ~ 1.3) is described.Yield：142mg (62%) colorless solid；LC/MS, Rt： 1.97min；(M+H) 340.1；1H NMR (400MHz, DMSO-d6) δ 7.58-7.52 (m, 3H), 7.52-7.45 (m, 2H), 7.38-7.31 (m, 1H), 6.87 (s, 1H), 4.73 (s, 2H), 4.09-3.90 (m, 2H), 2.91 (t, J=5.8Hz, 2H), 1.58 (s, 3H)。
Embodiment 4：
(R) three fluoro- 1- of -3,3,3- [1- (4- fluoro-phenyls) -1,4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases] -2- hydroxyls Base -2- methyl-propan -1- ketone (" A4 ")
Prepared as embodiment 1 (step 1.1 ~ 1.3) is described.Yield：102mg (77%) colorless solid；LC/MS, Rt： 2.02min；(M+H) 358.2；1H NMR (400MHz, DMSO-d6) δ 7.63-7.54 (m, 3H), 7.35-7.27 (m, 2H), 6.90 (s, 1H), 4.81-4.67 (m, 2H), 4.09-3.93 (m, 2H), 2.90 (t, J= 5.8Hz, 2H), 1.60 (s, 3H)。
Embodiment 5：
(R) -1- [1- (2,4- difluorophenyls) -1,4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases] -3,3,3- three is fluoro- 2- hydroxy-2-methyls-propane -1- ketone (" A5 ")
Prepared as embodiment 1 (step 1.1 ~ 1.3) is described.Yield：160mg (77%) light yellow solid；LC/MS, Rt： 1.99min；(M+H) 376.1；1H NMR (400MHz, DMSO-d6) δ 7.68-7.50 (m, 3H), 7.26 (t, J= 7.9Hz, 1H), 7.23-7.10 (m, 1H), 5.18-3.62 (m, 4H), 2.81-2.54 (m, 2H), 1.56 (s, 3H)。
Embodiment 6：
(R) -1- [2- (2,4- difluorophenyls) -2,4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases] -3,3,3- three is fluoro- 2- hydroxy-2-methyls-propane -1- ketone (" A6 ")
As described in embodiment 1 (step 1.2 ~ 1.3), pass through flash chromatography (Companion RF, 24g Si50 silica gel chromatographs Post) separating step 5.1 isomerism cyclisation product, be converted into embodiment 6.Yield：51mg (79%) colorless solid；LC/MS, Rt：2.09min；(M+H) 376.1；1H NMR (400MHz, DMSO-d6, 80℃) δ 7.95 (d, J=2.4Hz, 1H), 7.81-7.74 (m, 1H), 7.46-7.39 (m, 1H), 7.23-7.16 (m, 1H), 6.95 (s, 1H), 4.88- 4.73 (m, 2H), 4.15-3.95 (m, 2H), 2.82 (t, J=5.9Hz, 2H), 1.59 (s, 3H)。
Embodiment 7：
(R) -1- (the 1- tert-butyl groups -1,4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases) the fluoro- 2- hydroxyls -2- of -3,3,3- three Methyl-propan -1- ketone (" A7 ")
Prepared as embodiment 1 (step 1.1 ~ 1.3) is described.Yield：131mg (57%) yellow solid；LC/MS, Rt： 1.85min；(M+H) 320.2；1H NMR (500MHz, DMSO-d6) δ 7.23 (s, 1H), 7.15 (s, 1H), 5.07-3.61 (m, 4H), 3.07-2.80 (m, 2H), 1.52 (s, 12H)。
Embodiment 8：
(R) -1- (the 2- tert-butyl groups -2,4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases) the fluoro- 2- hydroxyls -2- of -3,3,3- three Methyl-propan -1- ketone (" A8 ")
As described in embodiment 1 (step 1.2 ~ 1.3), pass through preparative HPLC (Agilent 1260, chromatographic column：Waters SunFire C18,5 μm, 30 × 150mm) separating step 7.1 isomerism cyclisation product, be converted into embodiment 8.Yield： 16mg (26%) colorless solid；LC/MS, Rt：1.85min；(M+H) 320.1.
For the general reaction scheme of formula Ia compound, in Formulas I a, X=N, Y=CH, R2Represent CH3。
Embodiment 9：
(2R) -1- [1- (4- chlorphenyls) -7- methyl -6,7- dihydro -4H- pyrazolos [4,3-c] pyridine -5- bases] -3,3,3- three Fluoro- 2- hydroxy-2-methyls-propane -1- ketone (" A9 "), the mixture of diastereomer
9.1 3- [1- dimethylaminos -methyl- (E)-subunit] -5- methyl -4- oxo piperidine -1- t-butyl formates
N-Boc-3- methyl -4- piperidones (1.00g, 4.689mmol) is dissolved in double (dimethylamino) methane of tert-butoxy In (1.14g, 6.564mmol).By reaction bulb diaphragm seal, 30min is stirred in 100 DEG C.Reactant mixture is cooled to room Temperature, diluted with water (20mL), use ethyl acetate extraction.By the organic layer of merging salt water washing, Na is used2SO4Dry, by taking out It is drawn through and filters and be evaporated to dryness.Yellow oil (1.24g) is not further purified and is used for next step.
As described in embodiment 1 (step 1.1 ~ 1.3), step 9.2 ~ 9.4 are carried out.Yield：179mg (74%) colorless solid； LC/MS, Rt：2.22min；(M+H) 388.1；1H NMR (400MHz, DMSO-d6, 90℃) δ 7.62-7.52 (m, 5H), 6.91 (d, J=3.2Hz, 1H), 5.11-4.76 (m, 1H), 4.69 (dd, J=15.8, 8.9Hz, 1H), 3.95 (dd, J=13.1, 5.3Hz, 1H), 3.92-3.76 (m, 1H), 3.42 (h, J=6.2Hz, 1H), 1.63- 1.57 (m, 3H), 0.89 (dd, J=6.8Hz, 2.5Hz, 3H)。
Embodiment 10：
(R) -1- [(R) -1- (the chloro- phenyl of 4-) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases] -3 3, The fluoro- 2- hydroxy-2-methyls of 3- tri--propane -1- ketone (" A10 ")
Embodiment 11：
(R) -1- [(S) -1- (the chloro- phenyl of 4-) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases] -3,3, The fluoro- 2- hydroxy-2-methyls of 3- tri--propane -1- ketone (" A11 ")
Pass through SFC (chromatographic columns：ChiralCel OJ-H, eluent：CO2:Methanol -92:8) diastereomer of embodiment 9 is carried out Preparative separation.The fraction of merging is evaporated to dryness.Oily residue is dissolved in acetonitrile, is diluted with water and freezes.
“A10”：66mg colorless solids；LC/MS, Rt：2.22min；(M+H) 388.1；1H NMR (400MHz, DMSO-d6, 80°C) δ 7.68-7.47 (m, 4H), 6.94 (s, 1H), 5.08-4.55 (m, 2H), 4.08- 3.66 (m, 2H), 3.51-3.32 (m, 1H), 1.60 (s, 3H), 0.88 (d, J=6.8Hz, 3H)。
“A11”：68mg yellow solids；LC/MS, Rt：2.23min；(M+H) 388.1；1H NMR (400MHz, DMSO-d6, 80°C) δ 7.65-7.48 (m, 4H), 6.94 (s, 1H), 5.20-4.59 (m, 2H), 4.08- 3.66 (m, 2H), 3.52-3.30 (m, 1H), 1.58 (s, 3H), 0.87 (d, J=6.8Hz, 3H)。
Embodiment 12：
Three fluoro- 1- of (2R) -3,3,3- [1- (4- fluorophenyls) -7- methyl -6,7- dihydro -4H- pyrazolo [4,3-c] pyridines -5- Base] -2- hydroxy-2-methyls-propane -1- ketone (" A12 "), the mixture of diastereomer
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Yield：185mg (66%) colorless solid；LC/MS, Rt： 2.07min；(M+H) 372.2；1H NMR (400MHz, DMSO-d6, 80℃) δ 7.60-7.49 (m, 3H), 7.37- 7.27 (m, 2H), 6.96 (s, 1H), 5.17-4.77 (m, 1H), 4.68 (dd, J=15.7, 7.5Hz, 1H), 3.98-3.75 (m, 2H), 3.36 (h, J=6.2Hz, 1H), 1.58 (d, J=5.3Hz, 3H), 0.84 (dd, J= 6.8, 2.3Hz, 3H)。
Embodiment 13：
Three fluoro- 1- of (2R) -3,3,3- [2- (4- fluorophenyls) -7- methyl -6,7- dihydro -4H- pyrazolo [4,3-c] pyridines -5- Base] -2- hydroxy-2-methyls-propane -1- ketone (" A13 "), the mixture of diastereomer
As described in embodiment 9 (step 9.3 ~ 9.4), pass through flash chromatography (Companion RF, 24g Si50 silica gel chromatographs Post) separating step 12.1 isomerism cyclisation product, be converted into embodiment 13.Yield：29mg (75%) colourless powder；LC/ MS, Rt：2.20/2.22min；(M+H) 372.1；1H NMR (400MHz, DMSO-d6) δ 8.29-8.24 (m, 1H), 7.83-7.75 (m, 2H), 7.37-7.28 (m, 2H), 7.27-7.14 (m, 1H), 5.34-4.97 (m, 1H), 4.95-4.50 (m, 1H), 4.25-3.91 (m, 1H), 3.39-3.20 (m, 1H), 3.19-2.89 (m, 1H), 1.68-1.45 (m, 3H), 1.25 (d, J=5.8Hz, 3H)。
Embodiment 14：
(R) three fluoro- 1- of -3,3,3- [(R) -1- (4- fluoro-phenyls) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyrrole Pyridine -5- bases] -2- hydroxy-2-methyls-propane -1- ketone (" A14 ")
Embodiment 15：
(R) three fluoro- 1- of -3,3,3- [(S) -1- (4- fluoro-phenyls) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyrrole Pyridine -5- bases] -2- hydroxy-2-methyls-propane -1- ketone (" A15 ")
Pass through SFC (chromatographic columns：ChiralCel OJ-H, eluent：CO2:Methanol -95:5) diastereomeric of embodiment 12 is carried out The preparative separation of body.The fraction of merging is evaporated to dryness.Oily residue is dissolved in acetonitrile, is diluted with water and freezes.
“A14”：66mg colorless solids；LC/MS, Rt：2.07min；(M+H) 372.1；1H NMR (400MHz, DMSO-d6, 80°C) δ 7.64-7.52 (m, 2H), 7.51 (s, 1H), 7.38-7.22 (m, 2H), 6.92 (s, 1H), 5.18-4.50 (m, 2H), 4.00-3.58 (m, 2H), 3.50-3.20 (m, 1H), 1.58 (s, 3H), 0.84 (d, J=6.8Hz, 3H)。
“A15”：65mg colorless solids；LC/MS, Rt：2.08min；(M+H) 372.1；1H NMR (400MHz, DMSO-d6, 80°C) δ 7.64-7.53 (m, 2H), 7.51 (s, 1H), 7.39-7.23 (m, 2H), 6.91 (s, 1H), 5.16-4.56 (m, 2H), 4.19-3.58 (m, 2H), 3.44-3.27 (m, 1H), 1.57 (s, 3H), 0.83 (d, J=6.8Hz, 3H)。
For preparing the alternative method of " A14 " and " A15 "：Pass through SFC (chromatographic columns：ChiralCel OJ-H, Eluent：CO2:2- propyl alcohol -95:5) the preparative separation of the enantiomer of the cyclisation product (step 12.1) of Boc protections is completed.Such as " A9 " (step 9.3 ~ 9.4) are described, and two kinds of enantiomers are separately converted into " A14 " and " A15 ".
Embodiment 16：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three (7- methyl isophthalic acids-phenyl -1,4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] Pyridine -5- bases)-propane -1- ketone (" A16 "), the mixture of diastereomer
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Yield：176mg (78%) colorless solid；LC/MS, Rt： 2.02min；(M+H) 354.2；1H NMR (400MHz, DMSO-d6, 80℃) δ 7.56-7.48 (m, 5H), 7.46- 7.38 (m, 1H), 6.94 (s, 1H), 5.16-4.77 (m, 1H), 4.70 (dd, J=15.6, 6.6Hz, 1H), 4.02-3.73 (m, 2H), 3.41 (h, J=6.3Hz, 1H), 1.59 (d, J=5.0Hz, 3H), 0.85 (dd, J= 6.8, 2.7Hz, 3H)。
Embodiment 17：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three (7- methyl -2- phenyl -2,4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] Pyridine -5- bases)-propane -1- ketone (" A17 "), the mixture of diastereomer
As described in " A9 " (step 9.3 ~ 9.4), pass through flash chromatography (Companion RF, 24g Si50 silica gel chromatographic columns) point From the isomerism cyclisation product of step 16.1, embodiment 17 is converted into.Yield：41mg (71%) light yellow solid；LC/MS, Rt：2.16/2.18min；(M+H) 354.2；1H NMR (400MHz, DMSO-d6) δ 8.33-8.25 (m, 1H), 7.79-7.73 (m, 2H), 7.52-7.44 (m, 2H), 7.31-7.25 (m, 1H), 7.25-7.12 (m, 1H), 5.36-4.99 (m, 1H), 4.97-4.53 (m, 1H), 4.27-3.88 (m, 1H), 3.41-2.92 (m, 2H), 1.69-1.44 (m, 3H), 1.31-1.19 (m, 3H)。
Embodiment 18：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three ((R) -7- methyl isophthalic acids-phenyl -1,4,6,7- tetrahydrochysenes-pyrazolo [4, 3-c] pyridine -5- bases)-propane -1- ketone (" A18 ")
Embodiment 19：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three ((S) -7- methyl isophthalic acids-phenyl -1,4,6,7- tetrahydrochysenes-pyrazolo [4, 3-c] pyridine -5- bases)-propane -1- ketone (" A19 ")
Pass through SFC (chromatographic columns：ChiralCel OJ-H, eluent：CO2:Methanol -95:5) diastereomer of " A16 " is carried out Preparative separates.The fraction of merging is evaporated to dryness.Oily residue is dissolved in acetonitrile, is diluted with water and freezes.
“A18”：54mg colorless solids；LC/MS, Rt：2.02min；(M+H) 354.2；1H NMR (400MHz, DMSO-d6, 80°C) δ 7.57-7.45 (m, 5H), 7.45-7.33 (m, 1H), 6.92 (s, 1H), 5.32- 4.45 (m, 2H), 4.14-3.53 (m, 2H), 3.53 - 3.25 (m, 1H), 1.58 (d, 3H), 0.84 (d,J=6.8Hz, 3H)。
“A19”：63mg colorless solids；LC/MS, Rt：2.03min；(M+H) 354.1；1H NMR (400MHz, DMSO-d6, 80°C) δ 7.57-7.46 (m, 5H), 7.45-7.34 (m, 1H), 6.91 (s, 1H), 5.23- 4.51 (m, 2H), 4.10-3.59 (m, 2H), 3.50-3.31 (m, 1H), 1.57 (s, 3H), 0.83 (d, J= 6.8Hz, 3H)。
Embodiment 20：
(R) -1- [(R) -1- (2,4- difluorophenyls) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3- c] pyridine -5- Base] the fluoro- 2- hydroxy-2-methyls of -3,3,3- three-propane -1- ketone (" A20 ")
Embodiment 21：
(R) -1- [(S) -1- (2,4- difluorophenyls) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases] - The fluoro- 2- hydroxy-2-methyls of 3,3,3- tri--propane -1- ketone (" A21 ")
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Pass through SFC (chromatographic columns：ChiralPak AS-H, eluent： CO2:2- propyl alcohol -97:3) the preparative separation of diastereomer is carried out.The fraction of merging is evaporated to dryness.Oily residue is dissolved In acetonitrile, it is diluted with water and freezes.
“A20”：35mg colorless solids；LC/MS, Rt：2.09min；(M+H) 390.1；1H NMR (400MHz, DMSO-d6, 80°C) δ 7.68-7.53 (m, 2H), 7.53-7.40 (m, 1H), 7.33-7.14 (m, 1H), 6.97 (s, 1H), 5.32-4.36 (m, 2H), 4.22-3.47 (m, 2H), 3.25-2.87 (m, 1H), 1.60 (s, 3H), 0.82 (d, J=6.9Hz, 3H)。
“A21”：35mg colorless solids；LC/MS, Rt：2.10min；(M+H) 390.1；1H NMR (400MHz, DMSO-d6, 80°C) δ 7.67-7.54 (m, 2H), 7.53-7.40 (m, 1H), 7.27-7.18 (m, 1H), 6.96 (s, 1H), 5.08-4.49 (m, 2H), 4.21-3.44 (m, 2H), 3.19-2.96 (m, 1H), 1.58 (s, 3H), 0.81 (d, J=6.8Hz, 3H)。
Embodiment 22：
(R) -1- ((the R) -1- tert-butyl group -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases) -3,3,3- three Fluoro- 2- hydroxy-2-methyls-propane -1- ketone (" A22 ")
Embodiment 23：
(R) -1- ((the S) -1- tert-butyl group -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases) -3,3,3- three Fluoro- 2- hydroxy-2-methyls-propane -1- ketone (" A23 ")
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Pass through SFC (chromatographic columns：ChiralPak AD-H, eluent： CO2:2- methanol -92:8) the preparative separation of diastereomer is carried out.The fraction of merging is evaporated to dryness.Oily residue is dissolved In acetonitrile, it is diluted with water and freezes.
“A22”：52mg colorless solids；LC/MS, Rt：1.99min；(M+H) 334.2；1H NMR (400MHz, DMSO-d6, 80°C) δ 7.20 (s, 1H), 6.87 (s, 1H), 5.24 (s, 1H), 4.65 (s, 1H), 4.18 (d, J=15.5Hz, 1H), 3.51-3.25 (m, 1H), 3.11-2.93 (m, 1H), 1.59 (s, 3H), 1.56 (s, 9H),1.19 (d, J=6.7Hz, 3H)。
“A23”：42mg colorless solids；LC/MS, Rt：1.85min；(M+H) 334.2；1H NMR (400MHz, DMSO-d6, 80°C) δ 7.21 (s, 1H), 6.84 (s, 1H), 5.36-5.02 (m, 1H), 4.60 (d, J= 12.8Hz, 1H), 4.21 (d, J=16.0Hz, 1H), 3.40-3.32 (m, 1H), 3.07-2.98 (m, 1H), 1.59-1.53 (m, 12H), 1.19 (d, J=6.7Hz, 3H)。
Embodiment 24：
(R) three fluoro- 1- of -3,3,3- [(R) -1- (2- fluoro-phenyls) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyrrole Pyridine -5- bases] -2- hydroxy-2-methyls-propane -1- ketone (" A24 ")
Embodiment 25：
(R) three fluoro- 1- of -3,3,3- [(S) -1- (2- fluoro-phenyls) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyrrole Pyridine -5- bases] -2- hydroxy-2-methyls-propane -1- ketone (" A25 ")
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Pass through SFC (chromatographic columns：ChiralPak AS-H, eluent： CO2:2- propyl alcohol -90:10) the preparative separation of diastereomer is carried out.The fraction of merging is evaporated to dryness.Oily residue is dissolved In acetonitrile, it is diluted with water and freezes.
“A24”：43mg colorless solids；LC/MS, Rt：2.02min; (M+H) 372.1；1H NMR (400MHz, DMSO-d6, 90°C) δ 7.60-7.30 (m, 5H), 6.91 (s, 1H), 4.99-4.65 (m, 2H), 4.05- 3.71 (m, 2H), 3.16-3.05 (m, 1H), 1.59 (s, 3H), 0.81 (d, J=6.8Hz, 3H)。
“A25”：45mg colorless solids；LC/MS, Rt：2.03min；(M+H) 372.1；1H NMR (400MHz, DMSO-d6, 90°C) δ 7.61-7.32 (m, 5H), 6.90 (s, 1H), 4.95-4.66 (m, 2H), 4.13- 3.60 (m, 2H), 3.15-3.04 (m, 1H), 1.59 (d, J=1.2Hz, 3H), 0.80 (d, J=6.8Hz, 3H)。
Embodiment 26：
2- [(R) -7- methyl -5- (the fluoro- 2- hydroxy-2-methyls-propionos of (R) -3,3,3- three) -4,5,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -1- bases]-benzonitrile (" A26 ")
Embodiment 27：
2- [(S) -7- methyl -5- (the fluoro- 2- hydroxy-2-methyls-propionos of (R) -3,3,3- three) -4,5,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -1- bases]-benzonitrile (" A27 ")
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Pass through SFC (chromatographic columns：ChiralPak AD-H, eluent： CO2:Methanol (containing 0.5% diethylamine) -85:15) the preparative separation of diastereomer is carried out.The fraction of merging is evaporated to dryness. Oily residue is dissolved in acetonitrile, is diluted with water and freezes.
“A26”：23mg yellow solids；LC/MS, Rt：2.03min；(M+H) 379.1；1H NMR (400MHz, DMSO-d6, 90°C) δ 8.65 (s, 1H), 8.24 (dt, J=8.3, 1.1Hz, 1H), 7.85 (dt, J=8.7, 0.9Hz, 1H), 7.67-7.59 (m, 1H), 7.30 (ddd, J=7.9, 6.8, 0.9Hz, 1H), 7.04 (s, H), 4.83-4.63 (m, 2H), 3.96-3.85 (m, 1H), 3.71-3.56 (m, 1H), 3.08-2.94 (m, 1H), 1.63 (d, J=1.2Hz, 3H), 1.50 (d, J=6.9Hz, 3H)。
“A27”：32mg yellow solids；LC/MS, Rt：2.06min；(M+H) 379.1；1H NMR (400MHz, DMSO-d6, 90°C) δ 8.64 (s, 1H), 8.24 (dd, J=8.3, 1.2Hz, 1H), 7.85 (dd, J=8.7, 1.0Hz, 1H), 7.63 (ddd, J=8.4, 6.7, 1.2Hz, 1H), 7.34-7.27 (m, 1H), 7.08 (s, 1H), 4.86-4.67 (m, 2H), 3.96-3.87 (m, 1H), 3.65-3.50 (m, 1H), 3.13-3.02 (m, 1H), 1.68 (d, J=1.2Hz, 3H), 1.50 (d, J=6.9Hz, 3H)。
Embodiment 28：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three ((R) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyrrole Pyridine -5- bases)-propane -1- ketone (" A28 ")
Embodiment 29：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three ((S) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyrrole Pyridine -5- bases)-propane -1- ketone (" A29 ")
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Pass through preparative HPLC (Agilent 1260, chromatographic column： Waters SunFire C18,5 μm, 30 × 150mm) carry out diastereomer preparative separation.The fraction of merging is evaporated Into aqueous residue, with the NaHCO of saturation3Solution is adjusted to alkalescence, uses ethyl acetate extraction.The organic layer of merging is washed with salt Wash, use Na2SO4Dry, filter and be evaporated to dryness.Oily residue is dissolved in acetonitrile, is diluted with water and freezes.
“A28”：30mg colorless solids；LC/MS, Rt：1.42min；(M+H) 278.1；
“A29”：34mg colorless solids；LC/MS, Rt：1.46min；(M+H) 278.1.
Embodiment 30：
(R) the fluoro- 2- hydroxyls -1- of -3,3,3- three [(R) -1- (6- methoxv-pyridine -3- bases) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes - Pyrazolo [4,3-c] pyridine -5- bases] -2- methyl-propan -1- ketone (" A30 ")
Embodiment 31：
(R) the fluoro- 2- hydroxyls -1- of -3,3,3- three [(S) -1- (6- methoxv-pyridine -3- bases) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes - Pyrazolo [4,3-c] pyridine -5- bases] -2- methyl-propan -1- ketone (" A31 ")
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Pass through preparative HPLC (chromatographic columns：LuxAmylose-2, elution Liquid：Normal heptane:2- propyl alcohol -70:30) the preparative separation of diastereomer is carried out.The fraction of merging is evaporated to dryness.Oily is residual Slag is dissolved in acetonitrile, is diluted with water and is freezed.
“A30”：87mg colorless solids；LC/MS, Rt：1.93min；(M+H) 385.1；1H NMR (400MHz, DMSO-d6, 90°C) δ 8.32 (d, J=2.7Hz, 1H), 7.85 (dd, J=8.8, 2.7Hz, 1H), 7.54 (s, 1H), 6.95 (d, J=8.8Hz, 1H), 6.89 (s, 1H), 5.09-4.80 (m, 1H), 4.66 (d, J= 15.7Hz, 1H), 4.02-3.92 (m, 4H), 3.87-3.71 (m, 1H), 3.38-3.28 (m, 1H), 1.60 (d, J=1.2Hz, 3H), 0.88 (d, J=6.8Hz, 3H)。
“A31”：82mg colorless solids；LC/MS, Rt：1.93min；(M+H) 385.1；1H NMR (400MHz, DMSO-d6, 90°C) δ 8.32 (d, J=2.5Hz, 1H), 7.85 (dd, J=8.8, 2.8Hz, 1H), 7.54 (s, 1H), 6.95 (d, J=8.7Hz, 1H), 6.89 (s, 1H), 5.05-4.77 (m, 1H), 4.68 (d, J= 15.7Hz, 1H), 4.02-3.77 (m, 5H), 3.39-3.27 (m, 1H), 1.59 (d, J=1.1Hz, 3H), 0.88 (d, J=6.9Hz, 3H)。
Embodiment 32：
(R) three fluoro- 1- of -3,3,3- [(R) -1- (the fluoro- pyridine -2- bases of 3-) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3- C] pyridine -5- bases] -2- hydroxy-2-methyls-propane -1- ketone (" A32 ")
Embodiment 33：
(R) three fluoro- 1- of -3,3,3- [(S) -1- (the fluoro- pyridine -2- bases of 3-) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3- C] pyridine -5- bases] -2- hydroxy-2-methyls-propane -1- ketone (" A33 ")
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Pass through preparative HPLC (chromatographic columns：ChiralPak AD-H, are washed De- liquid：Normal heptane:2- propyl alcohol -85:15) the preparative separation of diastereomer is carried out.The fraction of merging is evaporated to dryness.By oily Residue is dissolved in acetonitrile, is diluted with water and is freezed.
“A32”：66mg colorless solids；LC/MS, Rt：1.82min；(M+H) 373.1；1H NMR (400MHz, DMSO-d6, 90°C) δ 8.41 (dt, J=4.7, 1.2Hz, 1H), 7.97 (ddd, J=10.0, 8.3, 1.5Hz, 1H), 7.65-7.55 (m, 2H), 6.93 (s, 1H), 5.07-4.68 (m, 2H), 3.97-3.77 (m, 2H), 3.44-3.34 (m, 1H), 1.60 (d, J=1.3Hz, 4H), 0.89 (d, J=6.8Hz, 4H)。
“A33”：65mg colorless solids；LC/MS, Rt：1.83min；(M+H) 373.1；1H NMR (400MHz, DMSO-d6, 90°C) δ 8.41 (dt, J=4.6, 1.2Hz, 1H), 7.98 (ddd, J=10.1 , 8.3, 1.4Hz, 1H), 7.66-7.56 (m, 2H), 6.92 (s, 1H), 5.00-4.73 (m, 2H), 4.10-3.72 (m, 2H), 3.44-3.33 (m, 1H), 1.59 (d, J=1.1Hz, 3H), 0.88 (d, J=6.8Hz, 3H)。
Embodiment 34：
(R) -1- [(R) -1- (3,5- Difluoro-pyridin -2- bases) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine - 5- yls] the fluoro- 2- hydroxy-2-methyls of -3,3,3- three-propane -1- ketone (" A34 ")
Embodiment 35：
(R) -1- [(S) -1- (3,5- Difluoro-pyridin -2- bases) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine - 5- yls] the fluoro- 2- hydroxy-2-methyls of -3,3,3- three-propane -1- ketone (" A35 ")
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Pass through SFC (chromatographic columns：ChiralPak AS-H, eluent： CO2:2- propyl alcohol (containing 0.5% diethylamine) -90:10) the preparative separation of diastereomer is carried out.The fraction of merging is evaporated to It is dry.Oily residue is dissolved in acetonitrile, is diluted with water and freezes.
“A34”：35mg colorless solids；LC/MS, Rt：1.94min；(M+H) 391.1；1H NMR (400MHz, DMSO-d6, 90℃, TFA) δ 8.37 (d, J=2.4Hz, 1H), 7.90 (dd, J=10.1 , 7.9Hz, 1H), 7.59 (s, 1H), 5.06-4.69 (m, 2H), 4.02-3.80 (m, 2H), 3.44-3.31 (m, 1H), 1.63 (s, 3H), 0.91 (d, J=6.8Hz, 3H).
“A35”：33mg colorless solids；LC/MS, Rt：1.95min；(M+H) 391.1；1H NMR (400MHz, DMSO-d6, 90℃) δ 8.55-8.37 (m, 1H), 8.14 (ddd, J=9.8, 8.3, 2.5Hz, 1H), 7.61 (s, 1H), 6.90 (s, 1H), 5.03-4.56 (m, 2H), 4.08-3.61 (m, 2H), 3.41-3.20 (m, 1H), 1.57 (s, 3H), 0.86 (d, J=6.8Hz, 3H)。
Embodiment 36：
(R) three fluoro- 1- of -3,3,3- [(R) -1- (the fluoro- 2- methoxy-pyrimidines -4- bases of 5-) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrrole Azoles simultaneously [4,3-c] pyridine -5- bases] -2- hydroxy-2-methyls-propane -1- ketone (" A36 ")
Embodiment 37：
(R) three fluoro- 1- of -3,3,3- [(S) -1- (the fluoro- 2- methoxy-pyrimidines -4- bases of 5-) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrrole Azoles simultaneously [4,3-c] pyridine -5- bases] -2- hydroxy-2-methyls-propane -1- ketone (" A37 ")
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Pass through SFC (chromatographic columns：GhiralPak AD-H, eluent： CO2:Methanol (containing 0.5% diethylamine) -85:15) the preparative separation of diastereomer is carried out.The fraction of merging is evaporated to dryness. Oily residue is dissolved in acetonitrile, is diluted with water and freezes.
“A36”：46mg colorless solids；LC/MS, Rt：1.99min；(M+H) 404.1；1H NMR (400MHz, DMSO-d6, 90°C, TFA) δ 8.62 (d, J=3.9Hz, 1H), 8.39 (s, 1H), 5.24 (d, J=16.4Hz, 1H), 4.68-4.36 (m, 2H), 3.99 (s, 3H), 3.28 (dd, J=13.1 , 9.0Hz, 1H), 3.20- 3.05 (m, 1H), 1.61 (d, J=1.2Hz, 3H), 1.29 (d, J=6.9Hz, 3H)。
“A37”：48mg colorless solids；LC/MS, Rt：1.96min；(M+H) 404.1；1H NMR (400MHz, DMSO-d6) δ 8.76 (d, J=3.9Hz, 1H), 8.50 (s, 1H), 7.33-7.06 (m, 1H), 5.41-5.02 (m, 1H), 5.02-4.51 (m, 1H), 4.24-3.89 (m, 4H), 3.39-2.93 (m, 2H), 1.72-1.38 (m, 3H), 1.24 (d, J=6.7Hz, 3H)。
Embodiment 38：
(R) the fluoro- 2- hydroxyls -1- of -3,3,3- three [(R) -1- (4- hydroxy-cyciohexyls) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases] -2- methyl-propan -1- ketone (" A38 ")
Embodiment 39：
(R) the fluoro- 2- hydroxyls -1- of -3,3,3- three [(S) -1- (4- hydroxy-cyciohexyls) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases] -2- methyl-propan -1- ketone (" A39 ")
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Pass through SFC (chromatographic columns：ChiralCel OJ-H, eluent： CO2:Methanol -90:10) the preparative separation of diastereomer is carried out.The fraction of merging is evaporated to dryness.Oily residue is dissolved in In acetonitrile, it is diluted with water and freezes.
“A38”：6mg colorless solids；LC/MS, Rt：1.66min；(M+H) 376.2；1H NMR (400MHz, DMSO- d6, 90℃) δ 7.21 (s, 1H), 6.82 (s, 1H), 5.21-4.95 (m, 1H), 4.39-4.25 (m, 2H), 4.15-4.05 (m, 1H), 3.98 (tt, J=10.7, 3.5Hz, 1H), 3.90-3.79 (m, 1H), 3.46-3.29 (m, 1H), 3.20-3.04 (m, 1H), 2.41-2.09 (m, 2H), 1.90-1.68 (m, 2H), 1.66-1.42 (m, 7H), 1.14 (d, J=6.8Hz, 3H)。
“A39”：7mg colorless solids；LC/MS, Rt：1.65min；(M+H) 376.2；1H NMR (400MHz, DMSO- d6, 90℃) δ 7.22 (s, 1H), 6.80 (s, 1H), 5.24-4.90 (m, 1H), 4.42-4.18 (m, 2H), 4.08 (d, J=2.8Hz, 1H), 3.99 (tt, J=10.9, 3.7Hz, 1H), 3.91-3.79 (m, 1H), 3.48- 3.30 (m, 1H), 3.21-3.08 (m, 1H), 2.41-2.11 (m, 2H), 1.88-1.73 (m, 2H), 1.68- 1.44 (m, 7H), 1.14 (d, J=6.8Hz, 3H)。
Embodiment 40：
(R) three fluoro- 1- of -3,3,3- [(R) -1- (the fluoro- pyridine -2- bases of 5-) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3- C] pyridine -5- bases] -2- hydroxy-2-methyls-propane -1- ketone (" A40 ")
Embodiment 41：
(R) three fluoro- 1- of -3,3,3- [(S) -1- (the fluoro- pyridine -2- bases of 5-) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3- C] pyridine -5- bases] -2- hydroxy-2-methyls-propane -1- ketone (" A41 ")
Prepared as " A9 " (step 9.1 ~ 9.4) are described.Pass through SFC (chromatographic columns：ChiralPak AS-H, eluent： CO2:Methanol -85:15) the preparative separation of diastereomer is carried out.The fraction of merging is evaporated to dryness.Oily residue is dissolved in In acetonitrile, it is diluted with water and freezes.
“A40”：44mg colorless solids；LC/MS, Rt：2.17min；(M+H) 373.2；1H NMR (400MHz, DMSO-d6, 90℃) δ 8.47-8.40 (m, 1H), 7.94-7.83 (m, 2H), 7.60 (s, 1H), 6.91 (s, 1H), 5.40-5.02 (s, 1H), 4.49-4.33 (m, 2H), 3.84-3.74 (m, 1H), 3.59- 3.37 (m, 1H), 1.62 (d, J=1.1Hz, 3H), 1.14 (d, J=6.7Hz, 3H)。
“A41”：35mg colorless solids；LC/MS, Rt：2.16min；(M+H) 373.2；1H NMR (400MHz, DMSO-d6, 90℃) δ 8.44 (d, J=2.8Hz, 1H), 7.95-7.84 (m, 2H), 7.61 (s, 1H), 6.88 (s, 1H), 5.30-5.00 (m, 1H), 4.48 (d, J=16.2Hz, 1H), 4.28 (dd, J=12.9, 3.8Hz, 1H), 3.84-3.73 (m, 1H), 3.67-3.43 (m, 1H), 1.59 (s, 3H), 1.13 (d, J=6.7Hz, 3H)。
Embodiment 42：
1- [(R) -1- (4- fluoro-phenyls) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- bases] -2- hydroxyls - 2- methyl-propan -1- ketone (" A42 ")
It is prepared by the alternative method according to the synthesis such as " 14 " and " A15 ".Protected in the Boc of separation enantiomerism After the cyclisation product (step 12.1) of shield, as described in " A9 " (step 9.3 ~ 9.4), BOC is carried out with 2- hydroxy-2-methyls-propionic acid It is deprotected and acylated.
“A42”：30mg colorless solids；LC/MS, Rt：1.82min；(M+H) 318.2；1H NMR (400MHz, DMSO-d6, 90℃) δ 7.60-7.54 (m, 2H), 7.52 (s, 1H), 7.36-7.28 (m, 2H), 5.18 (s, 1H), 4.85 (d, J=15.8Hz, 1H), 4.70 (d, J=15.8Hz, 1H), 3.95-3.78 (m, 2H), 3.40- 3.28 (m, 1H), 1.40 (s, 3H), 1.39 (s, 3H), 0.86 (d, J=6.8Hz, 3H)。
For the general reaction scheme of formula Ia compound, in Formulas I a, X=CH, Y=N, R2Represent H.
Embodiment 43：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three (3- phenyl -3,4,6,7- tetrahydro-imidazos simultaneously [4,5-c] pyridine -5- Base)-propane -1- ketone (" A43 ")
43.1 1,4,6,7- tetrahydro-imidazos simultaneously [4,5-c] pyridine -5- t-butyl formates
4,5,6,7- tetrahydrochysene -1H- imidazos [4,5-c] pyridines (500.0mg, 4.060mmol) are suspended in dry THF In (10.0mL), addition DIPEA (1.59mL, 9.338mmol) and 4- (dimethylamino) pyridine (99.2mg, 0.812mmol), di-tert-butyl dicarbonate (1.95g, 8.932mmol) is then added.By reactant mixture with methanol (2.0mL) Dilution, is stirred at room temperature 16h.Reactant mixture is diluted with ethyl acetate, with 0.5N HCl, the NaHCO of saturation3Solution and Salt water washing, uses Na2SO4Dry, by being filtered by suction and being evaporated to dryness.Residue is suspended in methanol (5.0mL), with 1N hydrogen Sodium hydroxide solution (0.32mL, 8.323mmol) processing.Reactant mixture is stirred into 20min at room temperature, is concentrated under vacuum into Aqueous residue.The residue is diluted with water, uses ethyl acetate extraction.By the organic layer of merging salt water washing, Na is used2SO4It is dry It is dry, by being filtered by suction and being evaporated to dryness.Yield：682.5mg (75%) yellow oil.
43.2 1- phenyl -1,4,6,7- tetrahydro-imidazos simultaneously [4,5-c] pyridine -5- t-butyl formates
Under argon gas by Isosorbide-5-Nitrae, 6,7- tetrahydro-imidazos simultaneously [4,5-c] pyridine -5- t-butyl formates (219.0mg, 0.981mmol), Phenyl boric acid (239.2mg, 1.962mmol) and copper acetate (II) (89.1mg, 0.490mmol) are suspended in dry methylene chloride In (4.0mL).Dry pyridine (158 μ L, 1.962mmol) is added, navy blue reactant mixture is stirred into 43h at room temperature.Enter One step adds phenyl boric acid (239.2mg, 1.962mmol), copper acetate (II) (89.1mg, 0.490mmol) and dried under argon gas Pyridine (158 μ L, 1.962mmol), stirs the mixture for 21h at room temperature.By reactant mixture dchloromethane, use 15% ammonia spirit and salt water washing, use Na2SO4Dry, by being filtered by suction and being evaporated to dryness.Pass through chromatography (Companion RF, 24g Si50 silica gel chromatographic columns) purifying oily residue, pass through preparative HPLC (Agilent1260, chromatographic column：Waters SunFire C18,5 μm, 30 × 150mm) separation isomers.The fraction of merging is flashed into aqueous residue, with saturation NaHCO3 solution is adjusted to alkalescence, uses ethyl acetate extraction.By the organic layer of merging salt water washing, Na is used2SO4Dry, filtering And it is evaporated to dryness.Yield：81mg (28%) colorless oil；LC/MS, Rt：1.65min；(M+H) 300.2.
As described in embodiment 9 (step 9.3 ~ 9.4), step 43.3 (BOC- deprotections) and 43.4 (acylations) are carried out.Production Rate：80.5mg (78%) colorless solid；LC/MS, Rt：1.38min；(M+H) 340.1；1H NMR (400MHz, DMSO-d6, 90℃) δ 7.80 (s, 1H), 7.59-7.50 (m, 2H), 7.48-7.41 (m, 3H), 6.89 (s, 1H), 4.83-4.62 (m, 2H), 4.14-3.93 (m, 2H), 2.73 (t, J=5.8Hz, 2H), 1.60 (s, 3H)。
Embodiment 44：
(R) three fluoro- 1- of -3,3,3- [1- (4- fluoro-phenyls) -1,4,6,7- tetrahydro-imidazos simultaneously [4,5-c] pyridine -5- bases] -2- hydroxyls Base -2- methyl-propan -1- ketone (" A44 ")
Prepared as embodiment 43 (step 43.1 ~ 43.4) is described.Yield：33mg (63%) colorless solid；LC/MS, Rt： 1.46min；(M+H) 358.2；1H NMR (400MHz, DMSO-d6) δ 7.86 (s, 1H), 7.56-7.49 (m, 2H), 7.42-7.33 (m, 2H), 7.21-7.08 (m, 1H), 5.05-4.82 (m, 1H), 4.56-4.38 (m, 1H), 4.25-3.97 (m, 1H), 3.93-3.68 (m, 1H), 2.82-2.57 (m, 2H), 1.66-1.43 (m, 3H)。
Embodiment 45：
(R) -1- [1- (the chloro- phenyl of 4-) -1,4,6,7- tetrahydro-imidazos simultaneously [4,5-c] pyridine -5- bases] the fluoro- 2- hydroxyls of -3,3,3- three Base -2- methyl-propan -1- ketone (" A45 ")
Prepared as " A43 " (step 43.1 ~ 43.4) are described.Yield：39mg (89%) colorless solid；LC/MS, Rt： 1.65min；(M+H) 374.1；1H NMR (400MHz, DMSO-d6) δ 7.91 (s, 1H), 7.63-7.56 (m, 2H), 7.55-7.48 (m, 2H), 7.15 (s, 1H), 5.03-4.41 (m, 2H), 4.27-3.68 (m, 2H), 2.85-2.61 (m, 2H), 1.67-1.47 (m, 3H)。
For the general reaction scheme of formula Ia compound, in Formulas I a, X=N, Y=N, R2Represent H.
Embodiment 46：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three (1- phenyl -1,4,6,7- tetrahydrochysenes-[1,2,3] triazol [4,5-c] Pyridine -5- bases)-propane -1- ketone (" A46 ")
46.1 (3- nitro-pyridine -4- bases)-aniline
By the chloro- 3- nitro-pyridines (1.50g, 9.177mmol) of 4-, aniline (1.02mL, 11.013mmol) and anhydrous sodium acetate (3.76g, 45.887mmol) is suspended in glacial acetic acid (7.50mL), and 14h is stirred in 130 DEG C.Compound is cooled to room temperature, inclined Note uses NaHCO into water3The aqueous solution neutralizes, and is extracted with dichloromethane.The organic layer of merging is dried with sodium sulphate, filtered, very Sky concentration.Residue is purified by flash chromatography (CombiFlashRF 200).Yield：1.90g (96%) yellow solid；LC/ MS, Rt：1.40min；(M+H) 216.1.
46.2 N4- phenyl-pyridin -3,4- diamines
Compound 46.1 (2.30g, 10.645mmol) is hydrogenated at room temperature in THF (30.0mL) using Pd-C (5%) 14h.Solution is filtered, is evaporated to dryness, residue is not further purified and is used for next step.Yield：1.91g (97%) nothing Color solid；LC/MS, Rt：1.13min；(M+H) 186.1.
46.3 1- phenyl -1H- [, 2,3] and triazol [4,5-c] pyridine
Compound 46.2 (500.0mg, 2.683mmol) is dissolved in hydrochloric acid (40.3mL, 4.025mmol), is cooled to 0 DEG C. While colourless precipitate is formed, the natrium nitrosum (280.5mg, 4.025mmol) being dissolved in water (5.0mL) is slowly added to. Suspension is stirred into 30min in 0 DEG C, is then allowed to warm to room temperature 14h.By the NaHCO of reactant mixture saturation3The aqueous solution Dilution, uses ethyl acetate extraction.By the organic layer of merging salt water washing, dried, filtered with sodium sulphate, is concentrated in vacuo.Pass through Flash chromatography (CombiFlashRF 200) purifies residue.Yield：496mg (94%) brown solid；LC/MS, Rt： 1.71min；(M+H) 197.1.
46.4 1- phenyl -4,5,6,7- tetrahydrochysenes -1H- [1,2,3] triazol [4,5-c] pyridines
Compound 46.3 (299.0mg, 1.524mmol) is dissolved in methanol (10.0mL), under room temperature and 2.9 ~ 3.2bar In hydrogenating 14h on Pd-C (5%).Reactant is filtered, is evaporated to dryness.Yield：305mg (100%) colorless oil；LC/MS, Rt：0.89min；(M+H) 201.1.
46.5 (R) -3,3,3-, three fluoro- 2- hydroxy-2-methyls -1- (1- phenyl -1,4,6,7- tetrahydrochysenes-[1,2,3] triazole And [4,5-c] pyridine -5- bases)-propane -1- ketone (" A46 ")
It is acylated as " A9 " (step 9.4) is described.Yield：378mg (72%) colorless solid；LC/MS, Rt：1.88min；(M +H) 341.1；1H NMR (400MHz, DMSO-d6, 90℃) δ 7.68-7.62 (m, 2H), 7.62-7.56 (m, 2H), 7.56-7.48 (m, 1H), 6.97 (s, 1H), 4.92 (s, 2H), 4.16-4.04 (m, 1H), 4.04- 3.94 (m, 1H), 2.94 (t, J=5.7Hz, 2H), 1.61-1.57 (m, 3H)。
Embodiment 47：
(R) three fluoro- 1- of -3,3,3- [1- (4- fluoro-phenyls) -1,4,6,7- tetrahydrochysenes-[1,2,3] triazol [4,5-c] pyridine -5- Base] -2- hydroxy-2-methyls-propane -1- ketone (" A47 ")
Prepared as " A46 " (step 46.1 ~ 46.5) are described.Yield：89mg (70%) colorless solid；LC/MS, Rt： 1.93min；(M+H) 359.0；1H NMR (400MHz, DMSO-d6, 90℃) δ 7.78-7.61 (m, 2H), 7.49- 7.34 (m, 2H), 6.97 (s, 1H), 4.91 (s, br, 2H), 4.17-3.93 (m, 2H), 2.91 (t, J= 5.7Hz, 2H), 1.69-1.47 (m, 3H)。
Embodiment 48：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three (3- phenyl -5,6- dihydros -8H- [1,2,4] triazol [4,3-a] pyrroles Piperazine -7- bases)-propane -1- ketone (" A48 ")
As described in " A9 " (step 9.4), by 3- phenyl -5,6,7,8- tetrahydrochysenes-[1,2,4] triazol [4,3-a] pyrazine (60.0mg, 0.300mmol) uses (R) -3,3,3- tri- fluoro- 2- hydroxy-2-methyls-propionic acid (52.1mg, 0.330mmol) coupling. Yield：78mg (77%) colorless solid；LC/MS, Rt：1.54min；(M+H) 341.2；1H NMR (400MHz, DMSO-d6, 80℃) δ 7.79-7.71 (m, 2H), 7.58-7.48 (m, 3H), 7.14 (s, 1H), 5.22-4.95 (m, 2H), 4.33-4.03 (m, 4H), 1.60 (s, 3H)。
Embodiment 49：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three (3- phenyl -5,6- dihydro -8H- imidazo [1,2-a] pyrazines -7- Base)-propane -1- ketone (" A49 ")
As described in " A9 " (step 9.4), by 3- phenyl -5,6,7,8- tetrahydro-imidazos simultaneously [1,2-a] pyrazine (50.0mg, 0.251mmol) use (R) -3,3,3- tri- fluoro- 2- hydroxy-2-methyls-propionic acid (43.6mg, 0.276mmol) coupling.Yield： 41mg (49%) colorless solid；LC/MS, Rt：1.36min；(M+H) 340.2；1H NMR (400MHz, DMSO-d6) δ 7.54-7.41 (m, 4H), 7.41-7.23 (m, 2H), 7.09 (s, 1H), 5.37-3.84 (m, 6H), 1.59 (s, 3H)。
For the general reaction scheme of formula Ib compound, in Formulas I b, X=N, Y=CH, R2Represent H.
Embodiment 50：
(R) the fluoro- 2- hydroxy-2-methyls -1- of -3,3,3- three (3- phenyl -5,6- dihydro -8H- imidazo [1,5-a] pyrazines -7- Base)-propane -1- ketone (" A50 ")
50.1 N- pyrazine -2- ylmethvl-benzamides
(pyrazine -2- bases) methylamine (500.0mg, 4.353mmol) is dissolved in dichloromethane (20.0mL) under argon gas, cooled down To 0 DEG C.N- ethyl isopropylamines (0.89mL, 5.223mmol) are added, then add chlorobenzoyl chloride (0.56mL, 4.788mmol). Reactant mixture is warming up to room temperature, stir 18h.By the NaHCO of reactant mixture saturation3Solution dilutes.Separate organic phase, Water layer is washed 3 times with dichloromethane.The organic layer of merging is dried with sodium sulphate, filters and is evaporated to dryness.Pass through quick color Spectrometry (Companion RF, 40g Si50 silica gel chromatographic columns) purifies residue.Yield：895mg (96%) yellow solid；LC/MS, Rt：1.36min；(M+H) 214.1.
50.2 3- phenyl imidazoles simultaneously [1,5-a] pyrazine
N- pyrazine -2- ylmethvl-benzamides (300.0mg, 1.353mmol) are dissolved in dry acetonitrile (25.0mL). POCl is added under nitrogen3(1.24mL, 13.534mmol), reactant mixture is heated into 4h in 85 DEG C.Reactant mixture is cooled down To room temperature, it is evaporated to dryness.By residue in DCM, frozen water and NaHCO3Diluted in solution.Organic layer is separated, is extracted with dichloromethane Water layer.The organic layer of merging is dried with sodium sulphate, filters and is evaporated to dryness.Yield：244mg (92%) brown oil；LC/ MS, Rt：1.40min；(M+H) 196.1.
50.3 3- phenyl -5,6,7,8- tetrahydro-imidazos simultaneously [1,5-a] pyrazine
Compound 50.2 (244.0mg, 1.249mmol) is dissolved in methanol (10.0mL), under room temperature and 2.8bar in 14h is hydrogenated on Pd-C (5%).Reactant is filtered and is evaporated to dryness.Yield：233mg (94%) yellow oil；LC/MS, Rt：0.32min；(M+H) 200.1.
50.4 (R) -3,3,3-, three fluoro- 2- hydroxy-2-methyls -1- (3- phenyl -5,6- dihydro -8H- imidazos [1,5-a] Pyrazine -7- bases)-propane -1- ketone (" A50 ")
As described in (the step 9.4) of embodiment 9, by compound 50.3 (233.0mg, 1.169mmol) (R) -3,3,3- tri- is fluoro- 2- hydroxy-2-methyls-propionic acid (43.6mg, 0.276mmol) coupling.Yield：171mg (43%) colorless solid；LC/MS, Rt： 1.25min；(M+H) 340.1；1H NMR (400MHz, DMSO-d6, 90℃) δ 7.73-7.68 (m, 2H), 7.51- 7.45 (m, 2H), 7.44-7.39 (m, 1H), 7.02 (s, 1H), 6.94-6.90 (m, 1H), 4.97 (s, 2H), 4.22 (t, J=5.3Hz, 2H), 4.18-4.05 (m, 2H), 1.66-1.58 (m, 3H)。
Embodiment 51：
(R) three fluoro- 1- of -3,3,3- [3- (4- fluoro-phenyls) -5,6- dihydro -8H- imidazos [1,5-a] pyrazine -7- bases] -2- hydroxyls Base -2- methyl-propan -1- ketone (" A51 ")
Prepared as " A50 " (step 50.1 ~ 50.4) are described.Yield：234mg (65%) colorless solid；LC/MS, Rt： 1.34min；(M+H) 358.0；1H NMR (400MHz, DMSO-d6, 90℃) δ 7.73 (ddd, J=8.3, 5.3, 2.4Hz, 2H), 7.27 (td, J=8.9, 2.1Hz, 2H), 7.01 (s, 1H), 6.90 (s, 1H), 4.95 (s, 2H), 4.24-4.01 (m, 4H), 1.61 (s, 3H)。
For the general reaction scheme of formula Ib compound, in Formulas I b, X=N, Y=CH, R2Represent CH3。
Embodiment 52：
(R) three fluoro- 1- of -3,3,3- [(R) -3- (4- fluoro-phenyls) -5- methyl -5,6- dihydro -8H- imidazos [1,5-a] pyrazine - 7- yls] -2- hydroxy-2-methyls-propane -1- ketone (" A52 ")
Embodiment 53：
(R) three fluoro- 1- of -3,3,3- [(S) -3- (4- fluoro-phenyls) -5- methyl -5,6- dihydro -8H- imidazos [1,5-a] pyrazine - 7- yls] -2- hydroxy-2-methyls-propane -1- ketone (" A53 ")
52.1 2- chloromethyl -6- Methyl-pyrazins
Under a nitrogen 2,6- dimethyl pyrazines (500.0mg, 4.623mmol) and N-chloro-succinimide (617.4mg, Carbon tetrachloride (12.5mL) is added in 4.531mmol), compound is heated to reflux.Addition dibenzoyl peroxide (22.2mg, 0.077mmol), by colorless suspension in the heating 3h shown in 85.N-chloro-succinimide (61.7mg, 0.453mmol) is added, Reactant is heated into 2h in addition, then stirs 14h at room temperature.Reactant is diluted with water, extracted with dichloromethane.It will merge Organic layer dried with sodium sulphate, filter, be concentrated in vacuo.Residue is purified by flash chromatography (CombiFlashRF 200). Yield：328mg (51%) colorless oil；LC/MS, Rt：1.35min；(M+H) 143.1/145.1.
52.2 2- (6- Methyl-pyrazin -2- ylmethyls)-iso-indoles -1,3- diketone
By compound 52.1 (310.0mg, 2.174mmol), sodium acid carbonate (219.0mg, 2.609mmol) and phthalyl Imide (403.0mg, 2.174mmol) is dissolved in DMF (4.0mL), and peony/brown solution is stirred at room temperature 14h.Mixture is concentrated, is diluted with water, uses ethyl acetate extraction.By the organic layer of merging salt water washing, done with sodium sulphate It is dry, filter, be concentrated in vacuo.Residue is purified by flash chromatography (CombiFlashRF).Yield：226mg (41%) is colourless solid Body；LC/MS, Rt：1.74min；(M+H) 254.1.
52.3 C- (6- Methyl-pyrazin -2- bases)-methylamine
While stirring, in 2- (6- Methyl-pyrazin -2- ylmethyls)-iso-indoles -1,3- diketone (1.57g, 6.191mmol) Ethanol (60.0mL) suspension in be slowly added to hydrazine hydrate (2.41mL, 49.531mmol), heat the mixture to 80 °C. Colourless solution is formed after 5min, become colorless suspension after 30min.Reactant mixture is further flowed back 6h, is cooled to room temperature, Diluted with water (80mL) and 0.1N NaOH (30mL), extracted with the mixture of methylene chloride-methanol (1/1).By having for merging Machine layer is dried with sodium sulphate, is filtered, and is concentrated in vacuo.Yield：417mg (55%) colorless oil；LC/MS, Rt：0.33min； (M+H) 124.2。
The fluoro- N- of 52.4 4- (6- Methyl-pyrazin -2- ylmethyls)-benzamide
Compound 52.3 (416.0mg, 3.378mmol) is dissolved in dichloromethane (15.0mL), cooled down in ice bath.Add Enter N- ethyl diisopropylamines (0.69mL, 4.053mmol) and 4- fluorobenzoyl chlorides (0.43mL, 3.547mmol), remove ice bath. Yellow solution is formed, stirs 4h.By the NaHCO of mixture saturation3The aqueous solution and water dilution.Organic phase is separated, uses dichloromethane Alkane washs water layer.The organic layer of merging is dried with sodium sulphate, filtered, is concentrated in vacuo.Pass through flash chromatography (CombiFlashRF 200) purification of crude product.Yield：728mg (88%) yellow solid；LC/MS, Rt：1.56min；(M+H) 246.1。
52.5 3- (4- fluoro-phenyls) -5- methyl-imidazoles simultaneously [1,5-a] pyrazine
Compound 52.4 (728.0mg, 2.967mmol) is dissolved in dry acetonitrile (40.1mL).Add POCl3 (2.77mL, 29.669mmol).Orange mixture is stirred into 18h in 95 DEG C.Reactant mixture is cooled to room temperature, uses water (150mL) carefully dilutes, and is neutralized with sodium acid carbonate.Organic phase is separated, water layer is washed with dichloromethane.By the organic layer of merging Dried, filtered with sodium sulphate, is concentrated in vacuo.Thick residue is purified by flash chromatography (CombiFlashRF 200).Yield： 617mg (91%) yellow solid；LC/MS, Rt：1.47min；(M+H) 228.1.
52.6 3- (4- fluoro-phenyls) -5- methyl -5,6,7,8- tetrahydro-imidazos simultaneously [1,5-a] pyrazine
Compound 52.5 (617.0mg, 2.713mmol) is dissolved in methanol (10.0mL), under room temperature and 3.0bar in 4h is hydrogenated on Pd-C (5%).Reactant is filtered, is evaporated to dryness.Yield：606mg (97%) rice white grease；LC/MS, Rt：0.34min；(M+H) 232.2.
52.7 (R) -3,3,3-, three fluoro- 1- [3- (4- fluoro-phenyls) -5- methyl -5,6- dihydro -8H- imidazos [1,5-a] Pyrazine -7- bases] -2- hydroxy-2-methyls-propane -1- ketone
As described in (the step 9.4) of embodiment 9, by compound 52.6 (606.0mg, 2.619mmol) (R) -3,3,3- tri- is fluoro- 2- hydroxy-2-methyls-propionic acid coupling.
Yield：576mg (59%) yellow oil
Pass through SFC (chromatographic columns：ChiralPak AD-H, eluent：CO2:Methanol -80:20) carry out diastereomer (" A52 " and " A53 ") preparative separation.The fraction of merging is evaporated to dryness.
“A52”：58mg colorless solids；LC/MS, Rt：1.45min；(M+H) 372.1；1H NMR (400MHz, DMSO-d6, 90℃) δ 7.76-7.68 (m, 2H), 7.32-7.24 (m, 2H), 7.03 (s, 1H), 6.92 (s, 1H), 5.51-5.23 (m, 1H), 4.81-4.72 (m, 1H), 4.63 (d, J=16.5Hz, 1H), 4.55 (d, J =13.7Hz, 1H), 3.63-3.53 (m, 1H), 1.60 (s, 3H), 1.08 (d, J=6.5Hz, 3H)。
“A53”：57mg colorless solids；LC/MS, Rt：1.43min；(M+H) 372.1；1H NMR (400MHz, DMSO-d6, 90℃) δ 7.74 -7.67 (m, 2H), 7.31-7.22 (m, 2H), 6.98 (s, 1H), 6.86 (s, 1H), 5.43-5.16 (m, 1H), 4.80-4.72 (m, 1H), 4.64 (d, J=16.4Hz, 1H), 4.51- 4.44 (m, 1H), 3.59 (d, J=12.1Hz, 1H), 1.58 (s, 3H), 1.08 (d, J=6.5Hz, 3H)。
Embodiment 54：
(R) -1- [(R) -3- (2,4- difluorophenyls) -5- methyl -5,6- dihydro -8H- imidazos [1,5-a] pyrazine -7- bases] - The fluoro- 2- hydroxy-2-methyls of 3,3,3- tri--propane -1- ketone (" A54 ")
Embodiment 55：
(R) -1- [(S) -3- (2,4- difluorophenyls) -5- methyl -5,6- dihydro -8H- imidazos [1,5-a] pyrazine -7- bases] - The fluoro- 2- hydroxy-2-methyls of 3,3,3- tri--propane -1- ketone (" A55 ")
Prepared as " A52 "/" A53 " (step 52.4 ~ 52.7) is described.Pass through SFC (chromatographic columns：ChiralPak AD-H, Eluent：CO2:Ethanol -88:12) the preparative separation of diastereomer is carried out.The fraction of merging is evaporated to dryness.
“A54”：333mg colorless solids；LC/MS, Rt：1.44min；(M+H) 390.2；1H NMR (400MHz, DMSO-d6, 90℃) δ 7.62-7.50 (m, 1H), 7.30 (td, J=10.2, 2.5Hz, 1H), 7.18 (td, J =8.4, 2.3Hz, 1H), 7.03 (s, 1H), 6.89 (s, 1H), 5.34 (br, 1H), 4.68 (d, J= 16.3Hz, 1H), 4.51-4.32 (m, 2H), 3.62 (d, J=11.8Hz, 1H), 1.59 (s, 3H), 0.99 (d, J=6.3Hz, 3H)。
“A55”：342mg colorless solids；LC/MS, Rt：1.42min；(M+H) 390.2；1H NMR (400MHz, DMSO-d6, 90℃) δ 7.67-7.46 (m, 1H), 7.30 (td, J=10.2, 2.5Hz, 1H), 7.18 (td, J =8.5, 2.4Hz, 1H), 7.00 (s, 1H), 6.91 (s, 1H), 5.29 (br, 1H), 4.69 (d, J= 16.5Hz, 1H), 4.46-4.31 (m, 2H), 3.66 (d, J=10.1Hz, 1H), 1.58 (s, 3H), 1.00 (d, J=6.4Hz, 3H)。
Embodiment 56：
(R) -1- [(S) -3- (3,5- Difluoro-pyridin -2- bases) -5- methyl -5,6- dihydro -8H- imidazo [1,5-a] pyrazines -7- Base] the fluoro- 2- hydroxy-2-methyls of -3,3,3- three-propane -1- ketone (" A56 ")
Embodiment 57：
(R) -1- [(R) -3- (3,5- Difluoro-pyridin -2- bases) -5- methyl -5,6- dihydro -8H- imidazo [1,5-a] pyrazines -7- Base] the fluoro- 2- hydroxy-2-methyls of -3,3,3- three-propane -1- ketone (" A57 ")
Prepared as " A52 "/" A53 " (step 52.4 ~ 52.7) is described.Pass through SFC (chromatographic columns：ChiralPak AD-H, Eluent：CO2:Ethanol (containing 0.5% diethylamine) -88:12) the preparative separation of diastereomer is carried out.By the fraction of merging It is evaporated to dryness.
“A56”：333mg colorless solids；LC/MS, Rt：1.43min；(M+H) 391.1；1H NMR (400MHz, DMSO-d6, 90℃) δ 8.54 (s, 1H), 8.04-7.82 (m, 1H), 7.11-6.90 (m, 2H), 5.35 (s, br, 1H), 5.15-5.01 (m, 1H), 4.70 (d, J =16.8Hz, 1H), 4.49 (d, J=13.6Hz, 1H), 3.60 (d, J=12.4Hz, 1H), 1.62-1.56 (m, 3H), 1.17 (d, J=6.5Hz, 3H)。
“A57”：342mg colorless solids；LC/MS, Rt：1.45min；(M+H) 391.1；1H NMR (400MHz, DMSO-d6, 90℃) δ 8.54 (d, J=2.3Hz, 1H), 7.99-7.87 (m, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 5.41 (s, br, 1H), 5.17-5.00 (m, 1H), 4.68 (d, J=16.7Hz, 1H), 4.56 (d, J=13.9Hz, 1H), 3.55 (d, J=12.8Hz, 1H), 1.61 (s, 3H), 1.17 (d, J=6.4Hz, 3H)。
Pharmacology data
Suppression of table 1 Formulas I a or Ib some representative compounds to PDHK
IC50：<0.3μΜ=A 0.3~3μΜ=B 3~50μΜ=C.
The compound shown in table 1 is preferred compounds of the invention.
Particularly preferred compound is 14,20,34,38,40,54 and 57.
Following examples are related to medicine：
Embodiment A：Injection vial
100g Formulas I a or Ib active component and 5g disodium hydrogen phosphate will be dissolved in 3L double distilled water using 2N hydrochloric acid Obtained solution is adjusted to pH 6.5, is sterile filtered, is transferred in injection vial, aseptically freezes, in aseptic condition Lower sealing.Each injection vial contains 5mg active component.
Embodiment B：Suppository
The mixing that will be made up of 20g Formulas I a or Ib active component and 100g soybean lecithin and 1400g cocoa butter Thing melts, and pours into mould, is allowed to cool down.Every piece of suppository contains 20mg active component.
Embodiment C：Solution
By 1g Formulas I a or Ib active component, 9.38g NaH in 940mL double distilled water2PO4·2H2O, 28.48g Na2HPO4·12H2O and 0.1g benzalkonium chloride prepares solution.PH is adjusted to 6.8, the solution is settled to 1L, passed through Radiation is sterilized.The solution can be used in the form of eye drops.
Embodiment D：Ointment
Aseptically 500mg Formulas I a or Ib active component are mixed with 99.5g vaseline.
Embodiment E：Tablet
Suppress in conventional manner by 1kg Formulas I a or Ib active component, 4kg lactose, 1.2kg farina, 0.2kg Talcum powder and 0.1kg magnesium stearate composition mixture, tablet is made so that the every active component containing 10mg.
Embodiment F：Tablet
The similarly compressed tablets with embodiment E, then in conventional manner with by sucrose, farina, talcum powder, tragacanth With the coating agent coating of dyestuff composition.
Embodiment G：Capsule
2kg Formulas I a or Ib active component are filled into hard gelatin capsule in conventional manner so that each capsule contains 20mg active component.
Embodiment H：Ampoule
1kg Formulas I a or Ib active component are dissolved in the solution obtained in 60L double distilled water to be sterile filtered, are transferred to peace In small jar, aseptically freeze, aseptically seal.Each ampoule contains 10mg active component.

Claims (12)

1. Formulas I a or Formulas I b compound and its pharmaceutically acceptable salt, dynamic isomer and stereoisomer, including its institute Proportional mixture：
Wherein,
X represents CH or N,
Y represents CH or N,
R1Represent H, A, (CH2)nAr、(CH2)nHet or Cyc,
R2Represent H or CH3,
Ar represents phenyl, and it is unsubstituted or with Hal, A, CN, OA, [C (R5)2]POH、[C(R5)2]pN(R5)2、NO2、[C (R5)2]pCOOR5、NR5COA、NR5SO2A、[C(R5)2]pSO2N(R5)2、S(O)nA、O[C(R5)2]mN(R5)2、NR5COOA、 NR5CON(R5)2And/or COA is monosubstituted, two substitute, three substitute, four substitute or five substitutions,
Het represents monocyclic or bicyclic saturation, undersaturated or aromatics the heterocycle with 1 ~ 4 N, O and/or S atom, and it is not It is substituted or with Hal, A, CN, OA, [C (R5)2]pOH、[C(R5)2]pN(R5)2、NO2、[C(R5)2]pCOOR5、NR5COA、 NR5SO2A、[C(R5)2]pSO2N(R5)2、S(O)nA、O[C(R5)2]mN(R5)2、NR5COOA、NR5CON(R5)2And/or COA is mono- takes Generation or two substitutions,
Cyc represents the cycloalkyl with 3,4,5,6 or 7 C- atoms, and it is unsubstituted or monosubstituted with OH,
A represents the non-branched or branched alkyl with 1 ~ 10 C- atom, wherein 1 or 2 CH- and/or CH not adjoined2- base can Substituted by N- atoms, O- atoms and/or S- atoms, and/or wherein 1 ~ 7 H- atom can be by R4Substitution,
R4F, Cl or OH are represented,
R5H or A ' is represented,
A ' represents the non-branched or branched alkyl with 1 ~ 6 C- atom, wherein 1 ~ 5 H- atom can be substituted by F,
Hal represents F, Cl, Br or I,
M represents 1,2,3 or 4,
N represents 0,1 or 2,
P represents 0,1,2,3 or 4,
On condition that
If X=CH, Y=N, or
If Y=CH, X=N.
2. the compound and its pharmaceutically acceptable salt of claim 1, dynamic isomer and stereoisomer, including it is all The mixture of ratio, wherein,
Ar represents phenyl, and it is unsubstituted or with Hal, A, CN and/or OA be monosubstituted, two substitutions, three substitutions, four substitutions or five takes Generation.
3. the compound and its pharmaceutically acceptable salt of claim 1 or 2, dynamic isomer and stereoisomer, including its The mixture of all proportions, wherein,
Het represent pyrimidine radicals, pyridine radicals, pyridazinyl, pyrazinyl, piperidyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazole radicals, Furyl, thienyl, pyrrole radicals, oxazolyl, isoxazolyls, triazolyl, oxadiazolyls or thiadiazolyl group, each of which is without taking Generation or with Hal, A and/or OA it is monosubstituted or two substitute.
4. the compound and its pharmaceutically acceptable salt of claim 1, dynamic isomer and stereoisomer, including it is all The mixture of ratio, wherein,
X represents CH or N,
Y represents CH or N,
R1Represent H, A, (CH2)nAr、(CH2)nHet or Cyc,
R2Represent H or CH3,
Ar represents phenyl, and it is unsubstituted or with Hal, A, CN and/or OA be monosubstituted, two substitutions, three substitutions, four substitutions or five takes Generation,
Het represent pyrimidine radicals, pyridine radicals, pyridazinyl, pyrazinyl, piperidyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazole radicals, Furyl, thienyl, pyrrole radicals, oxazolyl, isoxazolyls, triazolyl, oxadiazolyls or thiadiazolyl group, each of which is without taking Generation or with Hal, A and/or OA it is monosubstituted or two substitute,
Cyc represents the cycloalkyl with 3,4,5,6 or 7 C- atoms, and it is unsubstituted or monosubstituted with OH,
A represents the non-branched or branched alkyl with 1 ~ 10 C- atom, wherein 1 or 2 CH- and/or CH not adjoined2- base can Substituted by N- atoms, O- atoms and/or S- atoms, and/or wherein 1 ~ 7 H- atom can be by R4Substitution,
R4F, Cl or OH are represented,
Hal represents F, Cl, Br or I,
N represents 0,1 or 2,
On condition that
If X=CH, Y=N, or
If Y=CH, X=N.
5. the compound and its pharmaceutically acceptable salt of claim 1, dynamic isomer and stereoisomer, including it is all The mixture of ratio, it is selected from following compound:
。
6. the Formulas I a or Ib of claim 1 ~ 5 compound and its pharmaceutically acceptable salt, dynamic isomer and alloisomerism The preparation method of body, it is characterised in that react Formula II a or IIb compound and the compound of formula III, and/or by Formulas I a or Ib alkali or acid are converted into one kind of its salt,
Wherein, X, Y, R1And R2With the implication as shown in claim 1；
Wherein, L represents the OH bases of Cl, Br, I or free or reactive function sex modification.
7. medicine, it is included：The Formulas I a or Ib compound and/or its pharmaceutically acceptable salt of at least one kind of claim 1, Dynamic isomer and stereoisomer, include the mixture of its all proportions；With arbitrary pharmaceutically acceptable carrier, figuration Agent or carrier.
8. the Formulas I a or Ib of claim 1 compound and its pharmaceutically acceptable salt, dynamic isomer and stereoisomer, Mixture including its all proportions, it is used for cancer, diabetes, heart ischemia, insulin resistance syndrome, Metabolic syndrome Sign, hyperglycemia, dyslipidemia, atherosclerosis, heart failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondria Disease, the treatment and/or prevention of mitochondrial encephalomyopathy.
9. the compound of claim 8, it is used to treat and/or prevents to be selected from following disease：Head, neck, eye, mouth, throat, Esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, uterine neck, breast, ovary, testis Or other reproductive organs, skin, thyroid gland, blood, lymph node, kidney, liver, pancreas, brain, the cancer of central nervous system, entity Knurl, and blood-born tumor (blood-borne tumor).
10. medicine, it is included：The Formulas I a or Ib compound and/or its pharmaceutically acceptable salt of at least one kind of claim 1, Dynamic isomer and stereoisomer, include the mixture of its all proportions；With at least one kind of other active constituents of medicine.
11. external member (kit), it includes following individually bag：
(a) the Formulas I a of the claim 1 of effective dose or Ib compound and/or its pharmaceutically acceptable salt, dynamic isomer And stereoisomer, include the mixture of its all proportions, and
(b) the other active constituents of medicine of effective dose.
12. compound 1- [(R) -1- (4- fluoro-phenyls) -7- methyl isophthalic acids, 4,6,7- tetrahydrochysenes-pyrazolo [4,3-c] pyridine -5- Base] -2- hydroxy-2-methyls-propane -1- ketone (" A42 ") and its pharmaceutically acceptable salt, dynamic isomer and alloisomerism Body, include the mixture of its all proportions.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1165817A (en) * 1996-04-26 1997-11-26 阿迪尔公司 New inhibitors of metalloprotease, process for preparing them and pharmaceutical compositions containing them
CN102471341A (en) * 2009-07-09 2012-05-23 Irm责任有限公司 Compounds and compositions for the treatment of parasitic diseases
WO2014100533A1 (en) * 2012-12-21 2014-06-26 Bristol-Myers Squibb Company NOVEL SUBSTITUTED IMIDAZOLES AS CASEIN KINASE 1 δ/ε INHIBITORS
WO2015090496A1 (en) * 2013-12-17 2015-06-25 Merck Patent Gmbh N1-(3,3,3-trifluoro-2-hydroxo-2-methylpropionyl)-piperidine derivatives as inhibitors of pyruvate dehydrogenase kinase
WO2015091795A1 (en) * 2013-12-20 2015-06-25 Laboratorios Del Dr. Esteve S.A. Fused imidazolyl derivatives, their preparation and use as medicaments

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3423414A (en) 1966-01-13 1969-01-21 Ciba Geigy Corp Pyrazolopyridines
JP2003508509A (en) * 1999-09-04 2003-03-04 アストラゼネカ アクチボラグ Amides as inhibitors of pyruvate dehydrogenase
JP4504924B2 (en) * 2002-12-20 2010-07-14 メルク・シャープ・エンド・ドーム・コーポレイション 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment and prevention of diabetes
EP2310389B1 (en) 2008-05-22 2012-01-04 Amgen Inc. Heterocycles as protein kinase inhibitors
AR074797A1 (en) 2008-10-10 2011-02-16 Japan Tobacco Inc FLUORENE COMPOUND, PHARMACEUTICAL COMPOSITIONS, PDHK AND PDHK2 INHIBITORS, TREATMENT METHODS, USES OF THE SAME AND COMMERCIAL KIT
JP6062633B2 (en) 2009-01-28 2017-01-18 カラ セラピューティクス インコーポレイテッド Bicyclic pyrazoloheterocycles
JO3773B1 (en) * 2013-03-14 2021-01-31 Janssen Pharmaceutica Nv P2x7 modulators

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1165817A (en) * 1996-04-26 1997-11-26 阿迪尔公司 New inhibitors of metalloprotease, process for preparing them and pharmaceutical compositions containing them
CN102471341A (en) * 2009-07-09 2012-05-23 Irm责任有限公司 Compounds and compositions for the treatment of parasitic diseases
WO2014100533A1 (en) * 2012-12-21 2014-06-26 Bristol-Myers Squibb Company NOVEL SUBSTITUTED IMIDAZOLES AS CASEIN KINASE 1 δ/ε INHIBITORS
WO2015090496A1 (en) * 2013-12-17 2015-06-25 Merck Patent Gmbh N1-(3,3,3-trifluoro-2-hydroxo-2-methylpropionyl)-piperidine derivatives as inhibitors of pyruvate dehydrogenase kinase
WO2015091795A1 (en) * 2013-12-20 2015-06-25 Laboratorios Del Dr. Esteve S.A. Fused imidazolyl derivatives, their preparation and use as medicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THOMAS D. AICHER ET AL.: "Secondary Amides of (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic Acid as Inhibitors of Pyruvate Dehydrogenase Kinase", 《J. MED. CHEM.》 *

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